Autophagy in Spinocerebellar ataxia type 2, a dysregulated pathway, and a target for therapy

Spinocerebellar ataxia type 2 (SCA2) is an incurable and genetic neurodegenerative disorder. The disease is characterized by progressive degeneration of several brain regions, resulting in severe motor and non-motor clinical manifestations. The mutation causing SCA2 disease is an abnormal expansion of CAG trinucleotide repeats in the ATXN2 gene, leading to a toxic expanded polyglutamine segment in the translated ataxin-2 protein. While the genetic cause is well established, the exact mechanisms behind neuronal death induced by mutant ataxin-2 are not yet completely understood. Thus, the goal of this study is to investigate the role of autophagy in SCA2 pathogenesis and investigate its suitability as a target for therapeutic intervention. For that, we developed and characterized a new striatal lentiviral mouse model that resembled several neuropathological hallmarks observed in SCA2 disease, including formation of aggregates, neuronal marker loss, cell death and neuroinflammation. In this new model, we analyzed autophagic markers, which were also analyzed in a SCA2 cellular model and in human post-mortem brain samples. Our results showed altered levels of SQSTM1 and LC3B in cells and tissues expressing mutant ataxin-2. Moreover, an abnormal accumulation of these markers was detected in SCA2 patients’ striatum and cerebellum. Importantly, the molecular activation of autophagy, using the compound cordycepin, mitigated the phenotypic alterations observed in disease models. Overall, our study suggests an important role for autophagy in the context of SCA2 pathology, proposing that targeting this pathway could be a potential target to treat SCA2 patients.

A Case Report on Spinocerebellar Ataxia Type 2

Objectives: The purpose of this study was to investigate a case of a patient with spinocerebellar ataxia (SCA) type 2 whose condition improved following treatment with Korean medicine.Methods: A 25-year-old man, diagnosed with SCA type 2, was treated with herbal medicine (Yukmijiwhang-tang-gami), acupuncture, and physical treatment. The therapeutic effect was evaluated using the Berg Balance Scale (BBS) and gait status.Results: Following treatment, the BBS score increased, and gait ataxia improved.Conclusions: This case study suggests that Korean medicine could be effective for relieving symptoms of SCA type 2.

Association of the Level of Neurofilament Light With Disease Severity in Patients With Spinocerebellar Ataxia Type 2

Background and Objectives:Few biochemical markers have been identified in spinocerebellar ataxia type 2 (SCA2). This study aimed to determine the levels of neurofilament light (NfL) in patients with SCA2 and identify whether they were associated with disease severity.Methods:Participants were recruited from one medical center in China, and individuals with SCA2 were genetically diagnosed. NfL levels were assessed using the single molecule array method. Disease severity was evaluated using the Scale for the Assessment and Rating of Ataxia (SARA), the International Cooperative Ataxia Rating Scale (ICARS), and the Inventory of Non-Ataxia Symptoms (INAS). Cerebellum and brainstem volumes were calculated using neuroimaging measurements. We used Pearson’s correlation and partial correlation for correlation analyses.Results:Forty-nine manifest patients with SCA2, 10 preclinical individuals with SCA2 and 92 controls were enrolled. A high consistency was identified between serum and CSF NfL (r = 0.868, p < 0.0001). In individuals with SCA2, levels of serum NfL were associated with disease severity (SARA, r = 0.425, p = 0.003; ICARS, r = 0.383, p = 0.009; INAS, r = 0.390, p = 0.007; cerebellum volume, r = - 0.393, p = 0.024) after adjustment for age. NfL levels were higher close to the expected age of onset in preclinical individuals with SCA2 (R2 = 0.43, p = 0.04).Discussion:Levels of serum NfL were correlated with disease intensity in individuals with SCA2, and were higher close to the estimated age of onset in preclinical SCA2. Therefore, NfL is a potential serum biomarker of disease severity in SCA2.Classification of Evidence:This study provides Class II evidence that elevated NfL levels are associated with disease severity in individuals with SCA2.

Differentiation of Saccadic Eye Movement Signals

Saccadic electrooculograms are discrete biosignals that contain the instantaneous angular position of the human eyes as a response to saccadic visual stimuli. These signals are essential to monitor and evaluate several neurological diseases, such as Spinocerebellar Ataxia type 2 (SCA2). For this, biomarkers such as peak velocity, latency and duration are computed. To compute these biomarkers, we need to obtain the velocity profile of the signals using numerical differentiation methods. These methods are affected by the noise present in the electrooculograms, specially in subjects that suffer neurological diseases. This noise complicates the comparison of the differentiation methods using real saccadic signals because of the impossibility of establishing exact saccadic onset and offset points. In this work, we evaluate 16 differentiation methods by the design of an experiment that uses synthetic saccadic electrooculograms generated from parametric models of both healthy subjects and subjects suffering from Spinocerebellar Ataxia type 2 (SCA2). For these synthetic electrooculograms the exact velocity profile is known, hence we can use them as a reference for comparison and error computing for the tasks of saccade identification and saccade biomarker computing. Finally, we identify the best fitting method or methods for each evaluated task.

RNA toxicity and perturbation of rRNA processing in spinocerebellar ataxia type 2

BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by expansion of a CAG repeat in Ataxin-2 (ATXN2) gene. The mutant ATXN2 protein with a polyglutamine tract is known to be toxic and contributes to the SCA2 pathogenesis. OBJECTIVE: Here we tested the hypothesis that the mutant ATXN2 transcript with an expanded CAG repeat (expATXN2) is also toxic and contributes to SCA2 pathogenesis. METHODS: The toxic effect of expATXN2 transcripts on SK-N-MC neuroblastoma cells and primary mouse cortical neurons was evaluated by caspase 3/7 activity and nuclear condensation assay, respectively. RNA immunoprecipitation assay was performed to identify RNA binding proteins (RBPs) that bind to expATXN2 RNA. Quantitative PCR was used to examine if rRNA processing is disrupted in SCA2 and Huntington disease (HD) human brain tissue. RESULTS: expATXN2 RNA induces neuronal cell death, and aberrantly interacts with RBPs involved in RNA metabolism. One of the RBPs, transducin beta-like protein 3 (TBL3), involved in rRNA processing, binds to both expATXN2 and expanded huntingtin (expHTT) RNA in vitro. rRNA processing is disrupted in both SCA2 and HD human brain tissue. CONCLUSION: These findings provide the first evidence of a contributory role of expATXN2 transcripts in SCA2 pathogenesis, and further support the role expHTT transcripts in HD pathogenesis. The disruption of rRNA processing, mediated by aberrant interaction of RBPs with expATXN2 and expHTT transcripts, suggest a point of convergence in the pathogeneses of repeat expansion diseases with potential therapeutic implications.