Spinal Cerebellar Ataxia Research Articles

Why do we so rarely recognise and treat the primary progressive form of multiple sclerosis?

The primary progressive form of multiple sclerosis is characterised by a systematic increase in disability from the onset of the disease, usually without overlapping relapses. It is estimated that it accounts for 10–15% of all cases of multiple sclerosis, occurs with similar frequency in both sexes, and its symptoms appear at an older age, usually after 40. The initial manifestation usually consists of pyramidal symptoms and myelopathy. The most typical symptoms include progressive gait and sphincter function impairment. Symptoms of cerebellar syndrome, truncal syndromes, as well as visual and cognitive disturbances are less common. The clinical course with characteristic symptomatology resulting from the location of the changes primarily in the spinal cord, followed by the occurrence of initial symptoms, means that this form of multiple sclerosis requires careful differential diagnosis. It should be differentiated primarily from diseases causing lower limb paresis (myelopathy associated with vitamin B12 deficiency, amyotrophic lateral sclerosis, spinal cerebellar ataxia, neuromyelitis optica spectrum disorder, Wernicke’s encephalopathy, Lyme disease, and spinal cord tumours). The diagnosis of primary progressive multiple sclerosis should be guided by the current 2017 McDonald diagnostic criteria. Understanding these criteria and being aware of the differences from the most common relapsing-remitting form of multiple sclerosis can be helpful in speeding up the diagnosis and implementing effective treatment. Even though new treatment options have emerged in recent years, primary progressive multiple sclerosis is still little known and too rarely recognised.

Incidence of different pressure patterns of spinal cerebellar ataxia and analysis of imaging and genetic diagnosis.

Neurologists have a difficult time identifying sporadic cerebellar ataxia. Multiple system atrophy of the cerebellar type (MSA-C), spontaneous late cortical cerebellar atrophy, and prolonged alcohol use are a few possible causes. In a group of people with sporadic cerebellar ataxia that was not MSA-C, an autosomal-dominant spinocerebellar ataxia (SCA) mutation was recently discovered. Chinese single-hospital cohort will be used in this study to genetic screen for SCA-related genes. One hundred forty individuals with CA were monitored over 8 years. Thirty-one individuals had familial CA, 109 patients had sporadic CA, 73 had MSA-C, and 36 had non-MSA-C sporadic CA. In 28 of the 31 non-MSA-C sporadic patients who requested the test, we carried out gene analysis, including SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, SCA31, and dentatorubro-pallidoluysian atrophy (DRPLA). The control group consisted of family members of the patients. In 57% of the instances with spontaneous CA that were not MSA-C, gene abnormalities were discovered. The most frequent exception among individuals with sporadic CA was SCA6 (36%), followed by monsters in SCA1, 2, 3, 8, and DRPLA. In contrast, 75% of the patients with familial CA had gene abnormalities, the most frequent of which was SCA6 abnormality. The age of 69 vs 59 was higher, and the CAG repeat length was a minor age of 23 vs 25 in the former instances compared to the last one among individuals with SCA6 anomalies that were sporadic as opposed to familial cases. In sporadic CA, autosomal-dominant mutations in SCA genes, notably in SCA6, are common. Although the cause of the increased incidence of SCA6 mutations is unknown, it may be related to a greater age of onset and varied penetrance of SCA6 mutations.

Short tandem repeat expansions in sporadic amyotrophic lateral sclerosis and frontotemporal dementia

Pathogenic short tandem repeat (STR) expansions cause over 20 neurodegenerative diseases. To determine the contribution of STRs in sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), we used ExpansionHunter, REviewer, and polymerase chain reaction validation to assess 21 neurodegenerative disease-associated STRs in whole-genome sequencing data from 608 patients with sporadic ALS, 68 patients with sporadic FTD, and 4703 matched controls. We also propose a data-derived outlier detection method for defining allele thresholds in rare STRs. Excluding C9orf72 repeat expansions, 17.6% of clinically diagnosed ALS and FTD cases had at least one expanded STR allele reported to be pathogenic or intermediate for another neurodegenerative disease. We identified and validated 162 disease-relevant STR expansions in C9orf72 (ALS/FTD), ATXN1 [spinal cerebellar ataxia type 1 (SCA1)], ATXN2 (SCA2), ATXN8 (SCA8), TBP (SCA17), HTT (Huntington's disease), DMPK [myotonic dystrophy type 1 (DM1)], CNBP (DM2), and FMR1 (fragile-X disorders). Our findings suggest clinical and pathological pleiotropy of neurodegenerative disease genes and highlight their importance in ALS and FTD.

Abstract #1394329: An Association Between Stiff Person Syndrome and Type 1 Diabetes

Stiff-person syndrome (SPS) is a rare neuromuscular disorder characterized by progressive muscular spasms and rigidity. Anti-glutamic acid decarboxylase (anti-GAD) antibodies are found in type 1 diabetes mellitus (T1DM). Thirty percent of patients diagnosed with SPS have T1DM. This relationship infers that SPS and T1DM share pathogenetic features. We describe a case of a 66-year-old female with a history of SPS who developed T1DM soon after the diagnosis was made. A 66-year-old female with a history of SPS, T1DM, and discoid lupus was referred to our university endocrinology clinic for diabetes management. She had ataxia, loss of balance, and muscle stiffness since 2012. The patient was diagnosed with spinal cerebellar ataxia. She was not treated with any specific agents and continued to have left-sided muscle stiffness with preserved strength. She denied weakness, pain, paresthesia, or muscle atrophy but had difficulty ambulating due to rigidity. The diagnosis of SPS was made based on positive anti-GAD antibodies (normal < 0.02) and positive N-channel antibodies in April 2016. She required hospital admission one month later and received solumedrol and IVIG. Her HbA1c was 6.5% (normal < 5.7% of total Hgb), and glucose levels were between 200-300 mg/dL, which were treated with basal and bolus insulin. She was discharged home in May 2016 with no diabetic medications. The patient developed polyuria and polydipsia with 11 Ibs unintentional weight loss 20 days after hospital discharge. She was referred to the endocrine clinic in June 2016 for further workup. Her HbA1c was 11% with C-peptide less than 0.01 (normal 0.78-5.20 ng/mL). Basal and bolus insulin were initiated, and she remains on an insulin regimen. SPS affects an estimated one person per million per year. Decreased level of gamma amino butyric acid (GABA) in the central nervous system (CNS) in SPS has been implicated, which causes a loss of neural inhibition. Glutamic acid decarboxylase (GAD) is the main enzyme required for the GABA inhibitory pathway. Anti-GAD antibodies decrease inhibitory function within the CNS and cause increased muscle activities and subsequent muscle spasms. While most patients with T1DM do not develop SPS, most with anti-GAD-positive SPS will have or develop T1DM. Either SPS or T1DM may be diagnosed first. Awareness of these associations is essential for early diagnosis and treatment of these disorders.

The roles of NOP56 in cancer and SCA36.

NOP56 is a highly conserved nucleolar protein. Amplification of the intron GGCCTG hexanucleotide repeat sequence of the NOP56 gene results in spinal cerebellar ataxia type 36 (SCA36). NOP56 contains an N-terminal domain, a coiled-coil domain, and a C-terminal domain. Nucleolar protein NOP56 is significantly abnormally expressed in a number of malignant tumors, and its mechanism is different in different tumors, but its regulatory mechanism in most tumors has not been fully explored. NOP56 promotes tumorigenesis in some cancers and inhibits tumorigenesis in others. In addition, NOP56 is associated with methylation in some tumors, suggesting that NOP56 has the potential to become a tumor-specific marker. This review focuses on the structure, function, related signaling pathways, and role of NOP56 in the progression of various malignancies, and discusses the progression of NOP56 in neurodegenerative and other diseases.

Effects of Repetitive Transcranial Magnetic Stimulation on Cerebellar Metabolism in Patients With Spinocerebellar Ataxia Type 3

BackgroundSpinocerebellar ataxia type 3 (SCA3) is the most common autosomal dominant hereditary ataxia, and, thus far, effective treatment remains low. Repetitive transcranial magnetic stimulation (rTMS) can improve the symptoms of spinal cerebellar ataxia, but the mechanism is unclear; in addition, whether any improvement in the symptoms is related to cerebellar metabolism has not yet been investigated. Therefore, the purpose of this study was to investigate the effects of low-frequency rTMS on local cerebellar metabolism in patients with SCA3 and the relationship between the improvement in the symptoms and cerebellar metabolism.MethodsA double-blind, prospective, randomized, sham-controlled trial was carried out among 18 SCA3 patients. The participants were randomly assigned to the real stimulation group (n = 9) or sham stimulation group (n = 9). Each participant in both the groups underwent 30 min of 1 Hz rTMS stimulation (a total of 900 pulses), differing only in terms of stimulator placement, for 15 consecutive days. To separately compare pre- and post-stimulation data (magnetic resonance spectroscopy (MRS) data and the International Cooperative Ataxia Rating Scale (ICARS) score) in the real and sham groups, paired-sample t-tests and Wilcoxon’s signed-rank tests were used in the analyses. The differences in the ICARS and MRS data between the two groups were analyzed with independent t-tests and covariance. To explore the association between the changes in the concentration of cerebellar metabolism and ICARS, we applied Pearson’s correlation analysis.ResultsAfter 15 days of treatment, the ICARS scores significantly decreased in both the groups, while the decrease was more significant in the real stimulation group compared to the sham stimulation group (p < 0.001). The analysis of covariance further confirmed that the total ICARS scores decreased more dramatically in the real stimulation group after treatment compared to the sham stimulation group (F = 31.239, p < 0.001). The values of NAA/Cr and Cho/Cr in the cerebellar vermis, bilateral dentate nucleus, and bilateral cerebellar hemisphere increased significantly in the real stimulation group (p < 0.05), but no significant differences were found in the sham stimulation group (p > 0.05). The analysis of covariance also confirmed the greater change in the real stimulation group. This study also demonstrated that there was a negative correlation between NAA/Cr in the right cerebellar hemisphere and ICARS in the real stimulation group (r = − 0.831, p = 0.02).ConclusionThe treatment with rTMS over the cerebellum was found to induce changes in the cerebellar local metabolism and microenvironment in the SCA3 patients. The alterations may contribute to the improvement of the symptoms of ataxia in SCA3 patients.

Generation of two induced pluripotent stem cell lines, GZHMCi009-A and GZHMCi010-A, derived from peripheral blood mononuclear cells of two SCA3 patients with 14/74 CAG repeats of the ATXN3 mutation

Spinal cerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is the result of abnormal repeat amplification of CAG of the ATXN3 gene. It is one of the main types of autosomal dominant ataxia, with motor symptoms of cerebellar ataxia, mainly accompanied by non-motor symptoms, such as ocular symptoms, psychiatric symptoms, and nutritional disorders. Currently, no effective treatment is available for patients with SCA3. The construction of induced pluripotent stem cells (iPSCs) from two SCA3 patients (14/74 CAG repeats) will be an excellent tool for studying SCA3 disease mechanisms and for drug screening.

EP387: Genetic testing for spinocerebellar ataxias in pediatric patients

Spinal cerebellar ataxias (SCA) are a group of heterogenous autosomal dominant inherited disorders characterized by progressive loss of balance, coordination, and non-ataxia related symptoms. While the majority of patients with SCAs typically have an adult onset of symptoms, many children are having genetic testing for these disorders. Some SCAs (such as SCA7) have or may have a childhood onset. Early diagnosis may be important for genetic counselling and can be crucial for prognosis and treatment.

NeuroSask Active and Connected: A neurorehab 2-way knowledge mobilization initiative

<h3>Research Objectives</h3> To use a virtual program to mobilize evidence-based knowledge on physical activity, mental health, and social support. To also use this platform as an avenue to provide updates on rapidly changing COVID-19 information specific to neurological conditions, and to gain insight on the current needs and concerns of participants. <h3>Design</h3> Program evaluation post and follow up (1-year). <h3>Setting</h3> ‘NeuroSask Active and Connected' started as a COVID-19 virtual knowledge-mobilization program designed to share information on evidence-based health-promoting behaviours, and to support social-connectedness amongst individuals with neurological conditions. <h3>Participants</h3> The project targeted individuals with moderate disability from a neurological condition and was inclusive of wheelchair users. <h3>Interventions</h3> The primary activity was a 10-week virtual program that ran twice weekly and included an ‘Active' and a ‘Connected' portion. Program evaluation involved surveying participants at the end of the 10-weeks. Based on high uptake and positive participant feedback, the program was extended, and a one-year evaluation of the program was completed. <h3>Main Outcome Measures</h3> Program evaluation. <h3>Results</h3> 800 participants registered for the initial 10-week program; approximately 1200 participants are enrolled in the extended program. 325 participants completed the one-year evaluation. 70% of participants have multiple sclerosis, with the remaining participants affected by other neurological conditions including Parkinson's disease, spinal cord injury, stroke, traumatic brain injury, cerebral palsy, and spinal cerebellar ataxia. Level of enjoyment was rated at 97%, and 100% agreed it was important for the program to continue running. Only 10% reported preferring in-person programs even outside of the pandemic (74% preferred virtual and 16% no preference). Participant-reported benefits included improved: physical wellbeing (96%); mental wellbeing (87%); sense of support (80%); awareness of existing resources (73%) and symptom management (55%). <h3>Conclusions</h3> NeuroSask provided support at a time of uncertainty and while the usual community physical activity/rehab, and social support programs were unavailable. Based on the reach, relevance, relationships, and results, this project had a substantial impact on participants. <h3>Author(s) Disclosures</h3> No conflicts of interest.

Diagnosis of orthostatic tremor using smartphone accelerometry

BackgroundPrimary orthostatic tremor (OT) is a rare movement disorder characterized by a 13–18 Hz leg tremor, which arises when standing and is relieved by walking/sitting. Those affected generally do not fall, but experience fear of falling, lessened by ambulation. Because of its low amplitude, the tremor is not readily visible, and diagnosis requires confirmation with surface electromyography (sEMG). Recently, applications using the accelerometer feature of smartphones have been used to detect and quantify tremors, including OT, though the accuracy of smartphone accelerometry (SPA) in diagnosing OT is unknown.MethodsWe completed SPA in consecutive adults (18+ years), who presented to our neurology clinic with either subjective leg shakiness upon standing or unsteadiness when standing that lessened with ambulation, which comprised 59 of 2578 patients. We assessed tremor using the StudyMyTremor application on an iPhone 6 s adhered with tape to the patient’s tibialis anterior. Surface electromyography was completed on the same muscle. The primary outcome of this study was to determine SPA’s sensitivity and specificity in detecting OT compared with surface electromyography.ResultsFifty-nine patients with the following diagnoses were included: OT (6), Parkinson’s disease, Hereditary Spastic Paraplegia, orthostatic hypotension, essential tremor, spinal cerebellar ataxia, sensory ataxia and functional movement disorder. Smartphone accelerometry detected a 13–18 Hz tremor in 5 of 6 patients diagnosed with OT by sEMG with no false positives in other conditions, yielding a sensitivity of 83%, specificity of 100% in the cohort we studied.ConclusionsThough a larger sample size is desirable, preliminary data suggest that smartphone accelerometry is an alternative to surface electromyography in diagnosing OT.

Neuroimaging of Pediatric Cerebellum in Inherited Neurodegenerative Diseases

In the study of cerebellar degenerative diseases, morphologic imaging (computed tomography, CT and magnetic resonance imaging, MRI) is the most common examination. From the clinical and genetic point of view, cerebellar degenerative diseases include heterogeneous conditions in which MRI may show isolated cerebellar atrophy or cerebellar atrophy associated with other cerebellar or supratentorial abnormalities. Neuroradiological progression is often observed. In congenital disorders of glycosylation (CDG), for example, MRI may be normal, may demonstrate mild cerebellar atrophy or, in the advanced stages of the disease, marked atrophy of the cerebellar hemispheres and vermis associated with the abnormal signal intensity of the cerebellar cortex and white matter and brainstem hypotrophy. In spinal cerebellar ataxias (SCAs), very rare in the pediatric population, MRI may demonstrate isolated cerebellar atrophy or cerebellar and brainstem atrophy. MRI shows characteristic findings in other diseases, strongly suggesting a distinct disorder, such as neuroaxonal dystrophy, ARSACS, ataxia-telangiectasia, or precise mitochondrial diseases. An example of neurodegenerative disorder with prenatal onset is pontocerebellar hypoplasia (PCH). PCH represents a group of neurodegenerative disorders characterized by microcephaly, early cerebellar hypoplasia, and variable atrophy of the cerebellum and ventral pons, genetically divided into several subtypes. Cerebellar hypoplasia visible on MRI is often the first sign that suggests the clinical diagnosis. In most cases, the PCH subtype may demonstrate a characteristic pattern distinguishable at MRI. Selective involvement of the cerebellum, sometimes accompanied by brainstem or supratentorial abnormalities in different combinations, may help restrict the differential diagnosis and may address the specific molecular screening.

Quantile Regression Analysis of Depression and Clinical Symptom Degree in Chinese Patients with Spinocerebellar Ataxia Type 3

Spinal cerebellar ataxia type 3 is a common SCA subtype in the world. It is a neurodegenerative disease characterized by ataxia. Patients exhibit common neuropsychological symptoms such as depression and anxiety. Some patients have suicidal tendencies when they are severely depressed. So, it is very important to study the severity of depression and clinical symptoms (SARA), to find out the patient’s psychological state in time and to help patients actively respond to treatment. A total of 97 Chinese SCA3 patients were enrolled in the study. The Beck Depression Scale was used to investigate the prevalence of depression in the confirmed patients. The distribution of depression data in these patients was investigated. Then, the quantifier was used to model the depression status of Chinese SCA3 patients. An analysis was conducted to identify the key factors affecting depression under different quantiles. Studies have shown that SARA and gender are important factors affecting depression; the effect of initial SARA is small, then the degree of influence increases, and the degree of influence decreases in the later period, but it is always positively correlated with depression; the development of women’s SARA is gentler than that of men, and the degree of depression is lower than that of men.

Limits of using oligonucleotides for allele-selective inhibition at trinucleotide repeat sequences – targeting the CAG repeat within ataxin-1

Trinucleotide repeats are responsible for many genetic diseases. Previous studies have shown that duplex RNAs (dsRNAs) can be used to target expression of a mutant repeat allele while leaving expression of the wild-type allele untouched, creating opportunities for allele-selective inhibition and better therapeutic outcomes. In contrast to successes with other genes, we report here that we cannot achieve allele-selective inhibition when targeting the expanded CAG repeat within Ataxin-1 (ATXN1), the cause of spinal cerebellar ataxia-1 (SCA1). The most likely explanation for this unfavorable outcome is that the mean CAG repeat number within wild-type ATXN1 is relatively high compared to other trinucleotide repeat diseases. Because the wild-type repeat number is high, it is likely that there is poor discrimination between the mutant and wild-type repeat and less opportunity for allele-selective inhibition across the entire spectrum of mutations found in SCA1 patients. Our data support the conclusion that the potential for multiple cooperative binding interactions is a critical factor governing allele-selective recognition of trinucleotide repeat genes by duplex RNAs. These results should be helpful in predicting which diseases and which patients are most likely to benefit from allele-selective targeting of expanded repeats.

Role of Mutant TBP in Regulation of Myogenesis on Muscle Satellite Cells.

In polyglutamine (PolyQ) diseases, mutant proteins cause not only neurological problems but also peripheral tissue abnormalities. Among all systemic damages, skeletal muscle dystrophy is the severest. Previously by studying knock-in (KI) mouse models of spinal cerebellar ataxia 17 (SCA17), it was found that mutant TATA box binding protein (TBP) decreases its interaction with myogenic differentiation antigen, thus reducing the expression of skeletal muscle structural proteins and resulting in muscle degeneration. In this paper, the role of mutant TBP in myogenesis was investigated. Single myofibers were isolated from tibialis anterior muscles of wild type (WT) and SCA17KI mice. The 1TBP18 staining confirmed the expression of mutant TBP in muscle satellite cells in SCA17KI mice. In the BaCl2-induced TA muscle injury, H&E cross-section staining showed no significant change in myofibril size before and after BaCl2 treatment, and there was no significant difference in centralized nuclei between WT and SCA17KI mice, suggesting that mutant TBP had no significant effect on muscle regeneration. In the cultured primary myoblasts from WT and SCA17KI mice in vitro, representative BrdU immunostaining showed no significant difference in proliferation of muscle satellite cells. The primary myoblasts were then induced to differentiate and immunostained for eMyHC, and the staining showed there was no significant difference in differentiation of primary myoblasts between WT and SCA1KI mice. Our findings confirmed that mutant TBP had no significant effect on myogenesis.

First finding of familial spinal cerebellar Ataxia11 in China: clinical, imaging and genetic features

Spinal cerebellar ataxia 11 (SCA11) is a rare disease, characterized by progressive cerebellar ataxia, abnormal eye sign. Four families have been reported in the past. We report on China's first family with spinocerebellar ataxia 11. A careful investigation of the clinical manifestations, brain imaging, and exome and Sanger sequencing were utilized to identify pathogenic genetic variants in a three-generation pedigree that includes 5 affected individuals. The proband and affected members began to develop cerebellar ataxia, dysarthria, nystagmus, and strabismus at approximately age 40 for no apparent reason. The lifespan of patients in the family is shortened. Brain MRIs showed cerebellar atrophy and slight atrophy of the bulbar medulla. Electromyography showed extensive neurogenic damage. Sensory evoked potentials of lower limbs showed damage to the spinal-brainstem-cortical conduction pathway. Genetic analysis revealed a novel point mutation (c.3290T>C) in the TTBK2 gene encoding tau-microtubule kinase 2, which led to an amino acid exchange (p.Val1097Ala). The missense mutation segregated with the phenotype. The mutation has a very low mutation rate in the population, the variant amino acids are highly conserved among species, and protein function damage prediction at the mutation site is detrimental and is highly likely to cause protein damage. The pathogenicity prediction of the mutation site shows that it is likely to cause disease. This variation is consistent with the diagnosis of SCA11. The first SCA11-affected family in China was characterized by gait instability, movement disorders and dysarthria with obvious cerebellar atrophy. The pathogenic allele was a c.3290T>C mutation in the TTBK2 gene.

Profound analgesia is associated with a truncated peptide resulting from tissue specific alternative splicing of DRG CA8-204 regulated by an exon-level cis-eQTL.

Carbonic anhydrase-8 (CA8) is an intracellular protein that functions as an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1) critical to intracellular Ca++ release, synaptic functions and neuronal excitability. We showed previously that murine nociception and analgesic responses are regulated by the expression of this gene in dorsal root ganglion (DRG) associated with a cis-eQTL. In this report, we identify an exon-level cis-eQTL (rs6471859) that regulates human DRG CA8 alternative splicing, producing a truncated 1,697bp transcript (e.g., CA8-204). Our functional genomic studies show the “G” allele at rs6471859 produces a cryptic 3’UTR splice site regulating expression of CA8-204. We developed constructs to study the expression and function of the naturally occurring CA8-204G transcript (G allele at rs6471859), CA8-204C (C allele at rs6471859 reversion mutation) and CA8-201 (full length transcript). CA8-204G transcript expression occurred predominantly in non-neuronal cells (HEK293), while CA8-204C expression was restricted to neuronal derived cells (NBL) in vitro. CA8-204G produced a stable truncated transcript in HEK293 cells that was barely detectable in NBL cells. We also show CA8-204 produces a stable peptide that inhibits pITPR1 and Ca++ release in HEK293 cells. These results imply homozygous G/G individuals at rs6471859, which are common in the general population, produce exclusively CA8-204G that is barely detectable in neuronal cells. CA8 null mutations that greatly impact neuronal functions are associated with severe forms of spinal cerebellar ataxia, and our data suggest G/G homozygotes should display a similar phenotype. To address this question, we show in vivo using AAV8-FLAG-CA8-204G and AAV8-V5-CA8-201 gene transfer delivered via intra-neural sciatic nerve injection (SN), that these viral constructs are able to transduce DRG cells and produce similar analgesic and anti-hyperalgesic responses to inflammatory pain. Immunohistochemistry (IHC) examinations of DRG tissues further show CA8-204G peptide is expressed in advillin expressing neuronal cells, but to a lesser extent compared to glial cells. These findings explain why G/G homozygotes that exclusively produce this truncated functional peptide in DRG evade a severe phenotype. These genomic studies significantly advance the literature regarding structure-function studies on CA8-ITPR1 critical to calcium signaling pathways, synaptic functioning, neuronal excitability and analgesic responses.

In Silico Studies in Drug Research Against Neurodegenerative Diseases.

BackgroundNeurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis, Parkinson's disease (PD), spinal cerebellar ataxias, and spinal and bulbar muscular atrophy are described by slow and selective degeneration of neurons and axons in the central nervous system (CNS) and constitute one of the major challenges of modern medicine. Computer-aided or in silico drug design methods have matured into powerful tools for reducing the number of ligands that should be screened in experimental assays.MethodsIn the present review, the authors provide a basic background about neurodegenerative diseases and in silico techniques in the drug research. Furthermore, they review the various in silico studies reported against various targets in neurodegenerative diseases, including homology modeling, molecular docking, virtual high-throughput screening, quantitative structure activity relationship (QSAR), hologram quantitative structure activity relationship (HQSAR), 3D pharmacophore mapping, proteochemometrics modeling (PCM), fingerprints, fragment-based drug discovery, Monte Carlo simulation, molecular dynamic (MD) simulation, quantum-mechanical methods for drug design, support vector machines, and machine learning approaches.ResultsDetailed analysis of the recently reported case studies revealed that the majority of them use a sequential combination of ligand and structure-based virtual screening techniques, with particular focus on pharmacophore models and the docking approach.ConclusionNeurodegenerative diseases have a multifactorial pathoetiological origin, so scientists have become persuaded that a multi-target therapeutic strategy aimed at the simultaneous targeting of multiple proteins (and therefore etiologies) involved in the development of a disease is recommended in future.

Car8 dorsal root ganglion expression and genetic regulation of analgesic responses are associated with a cis-eQTL in mice.

Carbonic anhydrase-8 (Car8 mouse gene symbol) is devoid of enzymatic activity, but instead functions as an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1) to regulate this intracellular calcium release channel important in synaptic functions and neuronal excitability. Causative mutations in ITPR1 and carbonic anhydrase-8 in mice and humans are associated with certain subtypes of spinal cerebellar ataxia (SCA). SCA mice are genetically deficient in dorsal root ganglia (DRG) Car8 expression and display mechanical and thermal hypersensitivity and susceptibility to subacute and chronic inflammatory pain behaviors. In this report, we show that DRG Car8 expression is variable across 25 naïve-inbred strains of mice, and this cis-regulated eQTL (association between rs27660559, rs27706398, and rs27688767 and DRG Car8 expression; P < 1 × 10-11) is correlated with nociceptive responses in mice. Next, we hypothesized that increasing DRG Car8 gene expression would inhibit intracellular calcium release required for morphine antinociception and might correlate with antinociceptive sensitivity of morphine and perhaps other analgesic agents. We show that mean DRG Car8 gene expression is directly related to the dose of morphine or clonidine needed to provide a half-maximal analgesic response (r = 0.93, P < 0.00002; r = 0.83, P < 0.0008, respectively), suggesting that greater DRG Car8 expression increases analgesic requirements. Finally, we show that morphine induces intracellular free calcium release using Fura 2 calcium imaging in a dose-dependent manner; V5-Car8 WT overexpression in NBL cells inhibits morphine-induced calcium increase. These findings highlight the 'morphine paradox' whereby morphine provides antinociception by increasing intracellular free calcium, while Car8 and other antinociceptive agents work by decreasing intracellular free calcium. This is the first study demonstrating that biologic variability associated with this cis-eQTL may contribute to differing analgesic responses through altered regulation of ITPR1-dependent calcium release in mice.

Neurodegenerative disease: downsizing neurons.

Neuronal atrophy early in a mouse model of spinal cerebellar ataxia 1 may represent an adaptive mechanism that restores the density of potassium channels in Purkinje neurons, thus normalizing membrane polarization and firing.

Improved Sway Velocities and Directional Balance Improvement in Two Individuals with Spinal Cerebellar Ataxia with Balance-Based Torso-Weighting: A Case Series Report (P2.130)

Improved Sway Velocities and Directional Balance Improvement in Two Individuals with Spinal Cerebellar Ataxia with Balance-Based Torso-Weighting: A Case Series Report (P2.130)