Immunoresponsiveness in Ulcerative Colitis and Crohn's Disease—Effect of Colectomy and Suppression of Disease Activity

We evaluated the effect of medically induced symptomatic disease improvement on in vitro tests of cell-mediated immune responses in 33 patients with Crohn''s disease. When results obtained in 17 patients with ulcerative colitis were compared with those of 10 patients with ulcerative colitis who had undergone a colectomy, no significant correlation was detected between individual clinical and laboratory variables or the Crohn''s disease activity index and in vitro tests of cell-mediated immunity. A different pattern emerged from the longitudinal tests of cell-mediated immunity: when these test results were initially abnormal in patients with Crohn''s disease, clinical improvement as assessed by the Crohn''s disease activity index was associated with normalizing cell-mediated immunity. In contrast, when the test results were initially normal, clinical improvement was not associated with any change in the immune response. Following colectomy in patients with ulcerative colitis, some abnormalities of suppressed immune responses remained, although patients were cured of their disease. Factors other than clinical disease activity may be responsible for the suppressed immunoresponsiveness in some patients with inflammatory bowel disease, and variable changes in cell-mediated immunity occur after both surgical and medical treatment.     

Mechanisms of Neural and Behavioral Dysfunction in Alzheimer’s Disease

This review critically examines progress in understanding the link between Alzheimer’s disease (AD) molecular pathogenesis and behavior, with an emphasis on the impact of amyloid-β. We present the argument that the AD research field requires more multifaceted analyses into the impacts of Alzheimer’s pathogenesis which combine simultaneous molecular-, circuit-, and behavior-level approaches. Supporting this argument is a review of particular research utilizing similar, “systems-level” methods in mouse models of AD. Related to this, a critique of common physiological and behavioral models is made—highlighting the likely usefulness of more refined and specific tools in understanding the relationship between candidate molecular pathologies and behavioral dysfunction. Finally, we propose challenges for future research which, if met, may greatly extend our current understanding of how AD molecular pathology impacts neural network function and behavior and possibly may lead to refinements in disease therapeutics.     

Treatment of Anemia in Inflammatory Bowel Disease– Systematic Review and Meta-Analysis

Background

Anemia is considered the most common systemic complication of inflammatory bowel disease (IBD). We aimed to provide all available evidence regarding the safety and efficacy of therapy existing today to correct anemia in IBD.

Methods

Systematic review and meta-analysis of randomized controlled trials that compared any treatment for anemia in patients with IBD. We searched electronic databases, conference proceedings and clinical trials registries. Two reviewers independently extracted data from included trials. The primary outcome was the effect of treatment for anemia in IBD on the hemoglobin (Hb) response, defined as rate of patients who achieved an increase of 2 g/dl in Hb concentration at the end of the follow-up. Secondary outcomes included disease severity scores, iron indices, Hb levels, inflammatory markers, adverse effects, and mortality. Dichotomous data were analysed by calculating the relative risk (RR) for each trial with the uncertainty in each result being expressed using 95% confidence intervals (CI). A fixed effect model was used, except in the event of significant heterogeneity between the trials (P<0.10, I²>40%), in which we used a random effects model.

Results

Nine trials fulfilled the inclusion criteria, to a total of 973 patients. We were able to perform meta-analysis for intravenous (IV) versus oral iron and for ESAs versus placebo. IV iron was associated with a higher rate of achieving Hb response in comparison to oral iron; RR 1.25 (95% CI 1.04–1.51, I² = 2%, 4 trials), CRP levels and disease activity indexes were not significantly affected by IV iron. IV iron was associated with a decrease in adverse events that required discontinuation of intervention and without an increase in serious adverse.

Discussion

Treatment for anemia in IBD should include IV iron and not oral iron replacement, due to improved Hb response, no added toxicity and no negative effect on disease activity.     

Expression of Novel Alzheimer’s Disease Risk Genes in Control and Alzheimer’s Disease Brains

Late onset Alzheimer’s disease (LOAD) etiology is influenced by complex interactions between genetic and environmental risk factors. Large-scale genome wide association studies (GWAS) for LOAD have identified 10 novel risk genes: ABCA7, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A6A, MS4A6E, and PICALM. We sought to measure the influence of GWAS single nucleotide polymorphisms (SNPs) and gene expression levels on clinical and pathological measures of AD in brain tissue from the parietal lobe of AD cases and age-matched, cognitively normal controls. We found that ABCA7, CD33, and CR1 expression levels were associated with clinical dementia rating (CDR), with higher expression being associated with more advanced cognitive decline. BIN1 expression levels were associated with disease progression, where higher expression was associated with a delayed age at onset. CD33, CLU, and CR1 expression levels were associated with disease status, where elevated expression levels were associated with AD. Additionally, MS4A6A expression levels were associated with Braak tangle and Braak plaque scores, with elevated expression levels being associated with more advanced brain pathology. We failed to detect an association between GWAS SNPs and gene expression levels in our brain series. The minor allele of rs3764650 in ABCA7 is associated with age at onset and disease duration, and the minor allele of rs670139 in MS4A6E was associated with Braak tangle and Braak plaque score. These findings suggest that expression of some GWAS genes, namely ABCA7, BIN1, CD33, CLU, CR1 and the MS4A family, are altered in AD brains.     

Movement Preparation and Bilateral Modulation of Beta Activity in Aging and Parkinson’s Disease

In previous studies of young subjects performing a reaction-time reaching task, we found that faster reaction times are associated with increased suppression of beta power over primary sensorimotor areas just before target presentation. Here we ascertain whether such beta decrease similarly occurs in normally aging subjects and also in patients with Parkinson’s disease (PD), where deficits in movement execution and abnormalities of beta power are usually present. We found that in both groups, beta power decreased during the motor task in the electrodes over the two primary sensorimotor areas. However, before target presentation, beta decreases in PD were significantly smaller over the right than over the left areas, while they were symmetrical in controls. In both groups, functional connectivity between the two regions, measured with imaginary coherence, increased before the target appearance; however, in PD, it decreased immediately after, while in controls, it remained elevated throughout motor planning. As in previous studies with young subjects, the degree of beta power before target appearance correlated with reaction time. The values of coherence during motor planning, instead, correlated with movement time, peak velocity and acceleration. We conclude that planning of prompt and fast movements partially depends on coordinated beta activity of both sensorimotor areas, already at the time of target presentation. The delayed onset of beta decreases over the right region observed in PD is possibly related to a decreased functional connectivity between the two areas, and this might account for deficits in force programming, movement duration and velocity modulation.     

Alternations of Metabolic Profile and Kynurenine Metabolism in the Plasma of Parkinson’s Disease

The pathogenesis of Parkinson’s disease (PD) remains to be elucidated. Metabolomic analysis has the potential to identify biochemical pathways and metabolic profiles that are involved in PD pathogenesis. Here, we performed a targeted metabolomics to quantify the plasma levels of 184 metabolites in a discovery cohort including 82 PD patients and 82 normal controls (NCs) and found two up-regulated (dopamine, putrescine/ornithine ratio) and four down-regulated (octadecadienylcarnitine C18:2, asymmetric dimethylarginine, tryptophan, and kynurenine (KYN)) metabolites in the plasma of PD patients. We then measured the plasma levels of a panel of metabolic products of KYN pathway in an independent validation cohort including 118 PD patients, 22 Huntington’s disease (HD) patients, and 37 NCs. Lower kynurenic acid (KA)/KYN ratio, higher quinolinic acid (QA) level, and QA/KA ratio were observed in PD patients compared to HD patients and NCs. PD patients at advanced stage (Hoehn-Yahr stage >?2) showed lower KA and KA/KYN ratio, as well as higher QA and QA/KA ratio compared to PD patients at early stage (Hoehn-Yahr stage ≤?2) and NCs. Levels of KA and QA, as well as the ratios of KA/KYN and QA/KA between PD patients with and without psychiatric symptoms, dementia, or levodopa-induced dyskinesia in the advanced PD were similar. This metabolomic analyses demonstrate a number of plasma biomarker candidates for PD, suggesting a shift toward neurotoxic QA synthesis and away from neuroprotective KA production in KYN pathway.     

Role of Cholesterol in APP Metabolism and Its Significance in Alzheimer’s Disease Pathogenesis

Alzheimer’s disease (AD) is a complex multifactorial neurodegenerative disorder believed to be initiated by accumulation of amyloid β (Aβ)-related peptides derived from proteolytic processing of amyloid precursor protein (APP). Research over the past two decades provided a mechanistic link between cholesterol and AD pathogenesis. Genetic polymorphisms in genes regulating the pivotal points in cholesterol metabolism have been suggested to enhance the risk of developing AD. Altered neuronal membrane cholesterol level and/or subcellular distribution have been implicated in aberrant formation, aggregation, toxicity, and degradation of Aβ-related peptides. However, the results are somewhat contradictory and we still do not have a complete understanding on how cholesterol can influence AD pathogenesis. In this review, we summarize our current understanding on the role of cholesterol in regulating the production/function of Aβ-related peptides and also examine the therapeutic potential of regulating cholesterol homeostasis in the treatment of AD pathology.     

Twenty‐Four‐Hour and Annual Variation in Onset of Epistaxis in Osler Disease

Osler disease is an autosomal dominant disorder of the fibrovascular tissue characterized by arteriovenous malformations with multi‐systemic haemorrhages. Recurrent epistaxis is the predominant symptom in more than 90% of patients. Recent studies showed circadian and seasonal patterns in the onset of nosebleeds, similar to acute cardiovascular events, such as myocardial infarction and stroke. The aim of this study was to determine whether such patterns would also apply to the onset of epistaxis in patients with Osler disease. In all, 110 patients with Osler disease who were under treatment for recurrent epistaxis at the University Hospital of Mannheim were requested to complete a questionnaire addressing the intensity and frequency of epistaxis according to the classification of Bergler et al., as well as circadian and circannual rhythmicity in the occurrence of epistaxis according to visual analogue scales (VAS). More than half of the patients claimed to experience daily to weekly episodes of recurrent epistaxis. The occurrence of epistaxis showed a biphasic 24 h pattern, with a primary peak in the morning (05∶00–8∶00 h) and smaller secondary peaks in the evening (17∶00–20∶00 h and 21∶00–00∶00 h). No significant seasonal variation was found in the onset of epistaxis. However, a slight tendency, with a peak in winter months, was observed. Similar to other chronobiological studies on nosebleeds, this study showed that the 24 h pattern and seasonal tendency in the onset of epistaxis even applied to patients with Osler disease. Further investigations are necessary to determine the pathological mechanism underlying this phenomenon.     

Weight Loss and Impact on Quality of Life in Parkinson’s Disease

IntroductionWeight loss is common in Parkinson’s Disease (PD) and sometimes may precede the diagnosis. Weight loss is associated with multiple factors but its impact on health-related quality of life (HRQL) in PD remains unknown. We sought to investigate the factors associated with weight change and to quantify its effect on HRQL.MethodsThe National Parkinson Foundation Quality Improvement Initiative (NPF-QII) data was used to analyze PD patients longitudinally between two visits, separated by 12±6 months. Multiple linear regression analyses were used to assess the associations between baseline covariates and body weight change per month, and to evaluate whether, and to what degree, Parkinson’s Disease Questionnaire (PDQ-39) scores were affected.ResultsA higher Hoehn & Yahr stage, higher number of comorbidities, older age, lower MOCA estimate, and higher rate of levodopa usage were observed in patients who lost weight. Multivariate regression analysis indicated that age and levodopa usage were significantly associated with weight loss. Furthermore, monthly body weight loss was significantly associated with HRQL decline in PD patients. Loss of 1 lb (0.45 kg) per month was associated with a decline in QOL: an increase of 0.5% in PDQ-39 Summary Index score (p=0.004), and 1.1% and 1.5% increases in the mobility and ADL dimensions, respectively.ConclusionWeight loss in PD is common and seems to correlate with worsened HRQL. Awareness of factors associated with weight loss and its relation to HRQL may help practitioners improve patient management and expectations.     

Modulation of Molecular Chaperones in Huntington’s Disease and Other Polyglutamine Disorders

Polyglutamine expansion mutations in specific proteins underlie the pathogenesis of a group of progressive neurodegenerative disorders, including Huntington’s disease, spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and several spinocerebellar ataxias. The different mutant proteins share ubiquitous expression and abnormal proteostasis, with misfolding and aggregation, but nevertheless evoke distinct patterns of neurodegeneration. This highlights the relevance of the full protein context where the polyglutamine expansion occurs and suggests different interactions with the cellular proteostasis machinery. Molecular chaperones are key elements of the proteostasis machinery and therapeutic targets for neurodegeneration. Here, we provide a focused review on Hsp90, Hsp70, and their co-chaperones, and how their genetic or pharmacological modulation affects the proteostasis and disease phenotypes in cellular and animal models of polyglutamine disorders. The emerging picture is that, in principle, Hsp70 modulation may be more amenable for long-term treatment by promoting a more selective clearance of mutant proteins than Hsp90 modulation, which may further decrease the necessary wild-type counterparts. It seems, nevertheless, unlikely that a single Hsp70 modulator will benefit all polyglutamine diseases. Indeed, available data, together with insights from effects on tau and alpha-synuclein in models of Alzheimer’s and Parkinson’s diseases, indicates that Hsp70 modulators may lead to different effects on the proteostasis of different mutant and wild-type client proteins. Future studies should include the further development of isoform selective inhibitors, namely to avoid off-target effects on Hsp in the mitochondria, and their characterization in distinct polyglutamine disease models to account for client protein-specific differences.     

A Tale of Two Citrullines—Structural and Functional Aspects of Myelin Basic Protein Deimination in Health and Disease

Myelin basic protein (MBP) binds to negatively charged lipids on the cytosolic surface of oligodendrocyte membranes and is responsible for adhesion of these surfaces in the multilayered myelin sheath. The pattern of extensive post-translational modifications of MBP is dynamic during normal central nervous system (CNS) development and during myelin degeneration in multiple sclerosis (MS), affecting its interactions with the myelin membranes and with other molecules. In particular, the degree of deimination (or citrullination) of MBP is correlated with the severity of MS, and may represent a primary defect that precedes neurodegeneration due to autoimmune attack. That the degree of MBP deimination is also high in early CNS development indicates that this modification plays major physiological roles in myelin assembly. In this review, we describe the structural and functional consequences of MBP deimination in healthy and diseased myelin. Special issue dedicated to Drs. Anthony and Celia Campagnoni.     

Involvement of Endoplasmic Reticulum Stress in Inflammatory Bowel Disease: A Different Implication for Colonic and Ileal Disease?

Background

Endoplasmic reticulum (ER) stress has been suggested to play a role in inflammatory bowel disease (IBD). The three branches (ATF6, IRE1 and PERK) of the unfolded protein response (UPR) have different roles and are not necessarily activated simultaneously.

Methodology/Principal Findings

Expression of UPR-related genes was investigated in colonic and ileal biopsies of 23 controls, 15 ulcerative colitis (UC) and 54 Crohn''s disease (CD) patients. This expression was confirmed at protein level in colonic and ileal samples of five controls, UC and CD patients. HSPA5, PDIA4 and XBP1s were significantly increased in colonic IBD at mRNA and/or protein levels, indicating activation of the ATF6 and IRE1 branch. Colonic IBD was associated with increased phosphorylation of EIF2A suggesting the activation of the PERK branch, but subsequent induction of GADD34 was not observed. In ileal CD, no differential expression of the UPR-related genes was observed, but our data suggested a higher basal activation of the UPR in the ileal mucosa of controls. This was confirmed by the increased expression of 16 UPR-related genes as 12 of them were significantly more expressed in ileal controls compared to colonic controls. Tunicamycin stimulation of colonic and ileal samples of healthy individuals revealed that although the ileal mucosa is exhibiting this higher basal UPR activation, it is still responsive to ER stress, even more than colonic mucosa.

Conclusions/Significance

Activation of the three UPR-related arms is seen in colonic IBD-associated inflammation. However, despite EIF2A activation, inflamed colonic tissue did not increase GADD34 expression, which is usually involved in re-establishment of ER homeostasis. This study also implies the presence of a constitutive UPR activation in healthy ileal mucosa, with no further activation during inflammation. Therefore, engagement of the UPR differs between colon and ileum and this could be a factor in the development of ileal or colonic disease.     

Role of RAGE in Alzheimer’s Disease

Receptor for advanced glycation end products (RAGE) is a receptor of the immunoglobulin super family that plays various important roles under physiological and pathological conditions. Compelling evidence suggests that RAGE acts as both an inflammatory intermediary and a critical inducer of oxidative stress, underlying RAGE-induced Alzheimer-like pathophysiological changes that drive the process of Alzheimer’s disease (AD). A critical role of RAGE in AD includes beta-amyloid (Aβ) production and accumulation, the formation of neurofibrillary tangles, failure of synaptic transmission, and neuronal degeneration. The steady-state level of Aβ depends on the balance between production and clearance. RAGE plays an important role in the Aβ clearance. RAGE acts as an important transporter via regulating influx of circulating Aβ into brain, whereas the efflux of brain-derived Aβ into the circulation via BBB is implemented by LRP1. RAGE could be an important contributor to Aβ generation via enhancing the activity of β- and/or γ-secretases and activating inflammatory response and oxidative stress. However, sRAGE–Aβ interactions could inhibit Aβ neurotoxicity and promote Aβ clearance from brain. Meanwhile, RAGE could be a promoting factor for the synaptic dysfunction and neuronal circuit dysfunction which are both the material structure of cognition, and the physiological and pathological basis of cognition. In addition, RAGE could be a trigger for the pathogenesis of Aβ and tau hyper-phosphorylation which both participate in the process of cognitive impairment. Preclinical and clinical studies have supported that RAGE inhibitors could be useful in the treatment of AD. Thus, an effective measure to inhibit RAGE may be a novel drug target in AD.     

Mitochondria and Quality Control Defects in a Mouse Model of Gaucher Disease—Links to Parkinson’s Disease

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TETANUS—Prophylaxis and Treatment of the Disease

Cleansing and debridement is paramount in dealing with tetanus-prone wounds (severe crushing injuries, piercing wounds, blisters and burns are outstanding examples, particularly if contaminated with dirt, grass or other debris).Prophylaxis then is relatively easy in persons who have been actively immunized by toxoid injections. For them, a “booster” injection is indicated.Use of antitoxin, however, is hazardous, whether for prophylaxis or for treatment of the disease. Since it may in itself cause severe disease, including anaphylactic reaction and serum sickness, decision to use it must be weighed against the possibility of the development of tetanus in each case.To prepare for use of it, careful history should be taken, with particular reference to sensitivity to horse dander. Dermal tests, and perhaps ophthalmic tests, for sensitivity to the serum should be carried out. Even the tests may be hazardous and precautions should be taken accordingly.If it is decided that the use of antitoxin is necessary even though the patient is sensitive to the material, desensitization must be carried out promptly, with adequate preparation for severe reaction.There is experimental evidence that antibiotics of the tetracycline group, given soon after injury, may have prophylactic effect against tetanus.     

Azadiradione Restores Protein Quality Control and Ameliorates the Disease Pathogenesis in a Mouse Model of Huntington’s Disease

Huntington’s disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by expansion of CAG repeats in the coding area of huntingtin gene. In the HD brain, mutant huntingtin protein goes through proteolysis, and its amino-terminal portion consisting of polyglutamine repeats accumulate as inclusions that result in progressive impairment of cellular protein quality control system. Here, we demonstrate that partial rescue of the defective protein quality control in HD model mouse by azadiradione (a bioactive limonoids found in the seed of Azadirachta indica) could potentially improve the disease pathology. Prolonged treatment of azadiradione to HD mice significantly improved the progressive deterioration in body weight, motor functioning along with extension of lifespan. Azadiradione-treated HD mice brain also exhibited considerable decrease in mutant huntingtin aggregates load and improvement of striatal pathology in comparison with age-matched saline-treated HD controls. Biochemical analysis further revealed upregulation and activation of not only HSF1 (master regulator of protein folding) but also Ube3a (an ubiquitin ligase involved in the clearance of mutant huntingtin) in azadiradione-treated mice. Our results indicate that azadiradione-mediated enhanced folding and clearance of mutant huntingtin might underlie improved disease pathology in HD mice and suggests that it could be a potential therapeutic molecule to delay the progression of HD.     

Paraoxonase and Arylesterase Levels in Behcet’s Disease and Their Relations with the Disease Activity

The aim of this study was to determine the paraoxonase (PON) and arylesterase (ARE) enzyme activity levels in Behcet’s disease (BD) and to investigate whether they are associated with the disease activity. Twenty-six patients (study group) with active BD and 28 healthy controls (control group) were included in this study. While the patients who had at least one of the symptoms related to genital ulcer, skin lesions, active uveitis, arthritis, thrombophlebitis, or central nervous system involvement in addition to oral ulcers were considered as the active group, the patients who did not show clinical symptoms in the last one month due to the medical treatment were considered as the inactive group in the clinical evaluation of patients with BD. The PON and ARE levels were found to be significantly lower in the study group than the control group (p < 0.05). The PON levels of the active and inactive groups were 96.23 ± 57.84 and 112.2 ± 65.14, respectively. The ARE levels of the active and inactive groups were 30.49 ± 5.81 and 30.85 ± 6.40, respectively. No significant correlations were found between clinical findings and the activity levels of PON and ARE in the active patient group (p > 0.05). The activities of the antioxidant PON and ARE enzymes are reduced in BD. Therefore, it may be useful to add antioxidant therapy to the conventional treatment of the disease.     

Dynamics of Peripheral Blood Lymphocyte Subpopulations in the Acute and Subacute Phase of Legionnaires’ Disease

Study Objective

Absolute lymphocytopenia is recognised as an important hallmark of the immune response to severe infection and observed in patients with Legionnaires’ disease. To explore the immune response, we studied the dynamics of peripheral blood lymphocyte subpopulations in the acute and subacute phase of LD.

Methods and Results

EDTA-anticoagulated blood was obtained from eight patients on the day the diagnosis was made through detection of L. pneumophila serogroup 1 antigen in urine. A second blood sample was obtained in the subacute phase. Multiparametric flow cytometry was used to calculate lymphocyte counts and values for B-cells, T-cells, NK cells, CD4⁺ and CD8⁺ T-cells. Expression of activation markers was analysed. The values obtained in the subacute phase were compared with an age and gender matched control group. Absolute lymphocyte count (×10⁹/l, median and range) significantly increased from 0.8 (0.4–1.6) in the acute phase to 1.4 (0.8–3.4) in the subacute phase. B-cell count showed no significant change, while T-cell count (×10⁶/l, median and range) significantly increased in the subacute phase (495 (182–1024) versus 979 (507–2708), p = 0.012) as a result of significant increases in both CD4⁺ and CD8⁺ T-cell counts (374 (146–629) versus 763 (400–1507), p = 0.012 and 119 (29–328) versus 224 (107–862), p = 0.012). In the subacute phase of LD, significant increases were observed in absolute counts of activated CD4⁺ T-cells, naïve CD4⁺ T-cells and memory CD4⁺ T-cells. In the CD8⁺ T-cell compartment, activated CD8⁺ T-cells, naïve CD8⁺ T-cell and memory CD8⁺ T-cells were significantly increased (p<0.05).

Conclusion

The acute phase of LD is characterized by absolute lymphocytopenia, which recovers in the subacute phase with an increase in absolute T-cells and re-emergence of activated CD4⁺ and CD8⁺ T cells. These observations are in line with the suggested role for T-cell activation in the immune response to LD.     

Role of Inositol 1,4,5-Trishosphate Receptors in Pathogenesis of Huntington’s Disease and Spinocerebellar Ataxias

Huntington’s disease (HD) and spinocerebellar ataxias (SCAs) are autosomal-dominant neurodegenerative disorders. HD is caused by polyglutamine (polyQ) expansion in the amino-terminal region of a protein huntingtin (Htt) and primarily affects medium spiny striatal neurons (MSN). Many SCAs are caused by polyQ-expansion in ataxin proteins and primarily affect cerebellar Purkinje cells. The reasons for neuronal dysfunction and death in HD and SCAs remain poorly understood and no cure is available for the patients. Our laboratory discovered that mutant huntingtin, ataxin-2 and ataxin-3 proteins specifically bind to the carboxy-terminal region of the type 1 inositol 1,4,5-trisphosphate receptor (IP₃R1), an intracellular Ca²⁺ release channel. Moreover, we found that association of mutant huntingtin or ataxins with IP₃R1 causes sensitization of IP₃R1 to activation by IP₃ in planar lipid bilayers and in neuronal cells. These results suggested that deranged neuronal Ca²⁺ signaling might play an important role in pathogenesis of HD, SCA2 and SCA3. In support of this idea, we demonstrated a connection between abnormal Ca²⁺ signaling and neuronal cell death in experiments with HD, SCA2 and SCA3 transgenic mouse models. Additional data in the literature indicate that abnormal neuronal Ca²⁺ signaling may also play an important role in pathogenesis of SCAl, SCA5, SCA6, SCA14 and SCA15/16. Based on these results I propose that IP₃R and other Ca²⁺ signaling proteins should be considered as potential therapeutic targets for treatment of HD and SCAs.