Spinocerebellar Ataxia Type Research Articles

Factors Influencing Health-Related Quality of Life of Patients with Spinocerebellar Ataxia

BackgroundLittle is known about the progression of health-related quality of life (HRQoL) and predicting factors in spinocerebellar ataxia (SCA). Such knowledge is crucial to identify modifiable factors promoting everyday life with SCA and attenuating HRQoL decline.ObjectivesThis study is to assess HRQoL progression and identify factors affecting SCA patients’ HRQoL.MethodsLongitudinal data (three-year follow-up) of 310 SCA patients of the European SCA3/Machado-Joseph-Disease Initiative (ESMI) (2016-2022) and 525 SCA patients (SCA1, SCA2, SCA3 or SCA6) of the EUROSCA natural history study cohort (2006–2015) were assessed. Both large cohort studies share standardized assessments of clinical measures, SARA, INAS, PHQ-9, and HRQoL (EQ-5D-3L). The association between HRQoL and clinical measures was assessed by Spearman Correlation (rs). Multivariable panel regression models were performed to evaluate the impact of patients’ socio-demographics, age of onset, SCA type and body mass index (BMI), and clinical measures on HRQoL progression.ResultsHRQoL significantly decreased over one (− 0.014, p = 0.095), two (− 0.028, p = 0.003), and three years (− 0.032, p = 0.002). Ataxia severity and mental health strongly correlated with HRQoL (rsSARA = − 0.589; rsPHQ-9 = − 0.507). HRQoL more intensively declined in male (ß = − 0.024, p = 0.038) patients with an earlier age of onset (ß = 0.002, p = 0.058). Higher progression of ataxia severity (ß = − 0.010, p ≤ 0.001), mental health problems (ß = − 0.012, p < 0.001), and higher BMI (ß = − 0.003, p = 0.029) caused more severe decline of patients’ HRQoL over time.DiscussionIn absence of curative treatments, stronger focus on mental health and weight influence could help clinical evaluation and accompany treatment improving SCA patients’ HRQoL, especially in male patients with early disease onset.

Treatment with sodium butyrate induces autophagy resulting in therapeutic benefits for spinocerebellar ataxiatype 3.

Spinocerebellar ataxia type 3 (SCA3, also known as Machado Joseph disease) is a fatal neurodegenerative disease caused by the expansion of the trinucleotide repeat region within the ATXN3/MJD gene. Mutation of ATXN3 causes formation of ataxin-3 protein aggregates, neurodegeneration, and motor deficits. Here we investigated the therapeutic potential and mechanistic activity of sodium butyrate (SB), the sodium salt of butyric acid, a metabolite naturally produced by gut microbiota, on cultured SH-SY5Y cells and transgenic zebrafish expressing human ataxin-3 containing 84 glutamine (Q) residues to model SCA3. SCA3 SH-SY5Y cells were found to contain high molecular weight ataxin-3 species and detergent-insoluble protein aggregates. Treatment with SB increased the activity of the autophagy protein quality control pathway in the SCA3 cells, decreased the presence of ataxin-3 aggregates and presence of high molecular weight ataxin-3 in an autophagy-dependent manner. Treatment with SB was also beneficial invivo, improving swimming performance, increasing activity of the autophagy pathway, and decreasing the presence of insoluble ataxin-3 protein species in the transgenic SCA3 zebrafish. Co-treating the SCA3 zebrafish with SB and chloroquine, an autophagy inhibitor, prevented the beneficial effects of SB on zebrafish swimming, indicating that the improved swimming performance was autophagy-dependent. To understand the mechanism by which SB induces autophagy we performed proteomic analysis of protein lysates from the SB-treated and untreated SCA3 SH-SY5Y cells. We found that SB treatment had increased activity of Protein Kinase A and AMPK signaling, with immunoblot analysis confirming that SB treatment had increased levels of AMPK protein and its substrates. Together our findings indicate that treatment with SB can increase activity of the autophagy pathway process and that this has beneficial effects invitro and invivo. While our results suggested that this activity may involve activity of a PKA/AMPK-dependent process, this requires further confirmation. We propose that treatment with sodium butyrate warrants further investigation as a potential treatment for neurodegenerative diseases underpinned by mechanisms relating to protein aggregation including SCA3.

Nucleus accumbens degeneration in spinocerebellar ataxia type 2: a preliminary study.

Spinocerebellar ataxia type 2 (SCA2) exhibits mainly cerebellar and oculomotor dysfunctions but also, frequently, cognitive impairment and neuropsychological symptoms. The mechanism of the progression of SCA2 remains unclear. This study aimed to evaluate longitudinal structural changes in the brains of SCA2 patients based on atrophy rate. The OpenNeuro Dataset ds001378 was used. It comprises the demographic data and two magnetic resonance images each of nine SCA2 patients and 16 healthy controls. All structural images were preprocessed using FreeSurfer software, and each region's bilateral volume was summed. Atrophy rates were calculated based on the concept of symmetrised percent change and compared between SCA2 patients and healthy controls using non-parametric statistics. As post hoc analysis, correlation analysis was performed between infratentorial volume ratio and the accumbens area atrophy rates in SCA2 patients. There were no significant differences between groups for age, gender, and the time between scans. Statistical analysis indicated a significantly larger atrophy rate of the accumbens area in SCA2 patients than in controls. Additionally, the infratentorial volume ratio and accumbens area atrophy rates showed moderate negative correlation. This study found that nucleus accumbens (NAc) atrophy was significantly accelerated in SCA2 patients. Anatomically, the NAc is densely connected with infratentorial brain regions, so it is reasonable to posit that degeneration propagates from the cerebellum and brainstem to the NAc and other supratentorial areas. Functionally, the NAc is essential for appropriate behaviour, so NAc degeneration might contribute to neuropsychological symptoms in SCA2 patients.

The natural breakthrough: phytochemicals as potent therapeutic agents against spinocerebellar ataxia type 3

There is no FDA-approved drug for neurological disorders like spinocerebellar ataxia type 3. CAG repeats mutation in the ATXN3 gene, causing spinocerebellar ataxia type 3 disease. Symptoms include sleep cycle disturbance, neurophysiological abnormalities, autonomic dysfunctions, and depression. This research focuses on drug discovery against ATXN3 using phytochemicals of different plants. Three phytochemical compounds (flavonoids, diterpenoids, and alkaloids) were used as potential drug candidates and screened against the ATXN3 protein. The 3D structure of ATXN3 protein and phytochemicals were retrieved and validation of the protein was 98.1% Rama favored. The protein binding sites were identified for the interaction by CASTp. ADMET was utilized for the pre-clinical analysis, including solubility, permeability, drug likeliness and toxicity, and chamanetin passed all the ADMET properties to become a lead drug candidate. Boiled egg analysis attested that the ligand could cross the gastrointestinal tract. Pharmacophore analysis showed that chamanetin has many hydrogen acceptors and donors which can form interaction bonds with the receptor proteins. Chamanetin passed all the screening analyses, having good absorption, no violation of Lipinski’s rule, nontoxic properties, and good pharmacophore properties. Chamanetin was one of the lead compounds with a − 7.2 kcal/mol binding affinity after screening the phytochemicals. The stimulation of ATXN3 showed stability after 20 ns of interaction in an overall 50 ns MD simulation. Chamanetin (Flavonoid) was predicted to be highly active against ATXN3 with good drug-like properties. In-silico active drug against ATXN3 from a plant source and good pharmacokinetics parameters would be excellent drug therapy for SC3, such as flavonoids (Chamanetin).

A Case Report of Machado-Joseph Disease in Young Male Patient

Spinocerebellar ataxia type-3, also known as machado-joseph disease is an autosomal dominant CAG trinucleotide repeat disease that present in young to middle age adults.clinically, it is characterized by gradually progressive ataxia and progressive degenerative changes in cerebellum and spinal cord along with basal ganglia and cortex [1].

Longitudinal MRI and 1H-MRS study of SCA7 mouse forebrain reveals progressive multiregional atrophy and early brain metabolite changes indicating early neuronal and glial dysfunction.

SpinoCerebellar Ataxia type 7 (SCA7) is an inherited disorder caused by CAG triplet repeats encoding polyglutamine expansion in the ATXN7 protein, which is part of the transcriptional coactivator complex SAGA. The mutation primarily causes neurodegeneration in the cerebellum and retina, as well as several forebrain structures. The SCA7140Q/5Q knock-in mouse model recapitulates key disease features, including loss of vision and motor performance. To characterize the temporal progression of brain degeneration of this model, we performed a longitudinal study spanning from early to late symptomatic stages using high-resolution magnetic resonance imaging (MRI) and in vivo 1H-magnetic resonance spectroscopy (1H-MRS). Compared to wild-type mouse littermates, MRI analysis of SCA7 mice shows progressive atrophy of defined brain structures, with the striatum, thalamus and cortex being the first and most severely affected. The volume loss of these structures coincided with increased motor impairments in SCA7 mice, suggesting an alteration of the sensory-motor network, as observed in SCA7 patients. MRI also reveals atrophy of the hippocampus and anterior commissure at mid-symptomatic stage and the midbrain and brain stem at late stage. 1H-MRS of hippocampus, a brain region previously shown to be dysfunctional in patients, reveals early and progressive metabolic alterations in SCA7 mice. Interestingly, abnormal glutamine accumulation precedes the hippocampal atrophy and the reduction in myo-inositol and total N-acetyl-aspartate concentrations, two markers of glial and neuronal damage, respectively. Together, our results indicate that non-cerebellar alterations and glial and neuronal metabolic impairments may play a crucial role in the development of SCA7 mouse pathology, particularly at early stages of the disease. Degenerative features of forebrain structures in SCA7 mice correspond to current observations made in patients. Our study thus provides potential biomarkers that could be used for the evaluation of future therapeutic trials using the SCA7140Q/5Q model.

Adaptive Long-Read Sequencing Reveals GGC Repeat Expansion in ZFHX3 Associated with Spinocerebellar Ataxia Type 4.

Spinocerebellar ataxia type 4 (SCA4) is an autosomal dominant ataxia with invariable sensory neuropathy originally described in a family with Swedish ancestry residing in Utah more than 25 years ago. Despite tight linkage to the 16q22 region, the molecular diagnosis has since remained elusive. Inspired by pathogenic structural variation implicated in other 16q-ataxias with linkage to the same locus, we revisited the index SCA4 cases from the Utah family using novel technologies to investigate structural variation within the candidate region. We adopted a targeted long-read sequencing approach with adaptive sampling on the Oxford Nanopore Technologies (ONT) platform that enables the detection of segregating structural variants within a genomic region without a priori assumptions about any variant features. Using this approach, we found a heterozygous (GGC)n repeat expansion in the last coding exon of the zinc finger homeobox 3 (ZFHX3) gene that segregates with disease, ranging between 48 and 57 GGC repeats in affected probands. This finding was replicated in a separate family with SCA4. Furthermore, the estimation of this GGC repeat size in short-read whole genome sequencing (WGS) data of 21,836 individuals recruited to the 100,000 Genomes Project in the UK and our in-house dataset of 11,258 exomes did not reveal any pathogenic repeats, indicating that the variant is ultrarare. These findings support the utility of adaptive long-read sequencing as a powerful tool to decipher causative structural variation in unsolved cases of inherited neurological disease. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Abnormal cortical excitability in patients with spinocerebellar ataxia type 12

BackgroundSpinocerebellar ataxia type 12 (SCA-12) is an uncommon autosomal dominant cerebellar ataxia characterized by action tremors in the upper limbs, dysarthria, head tremor, and gait ataxia. We aimed to evaluate the motor cortical excitability in patients with SCA-12 using transcranial magnetic stimulation (TMS). MethodsThe study was done in the department of Neurology at the National Institute of Mental Health and Neuro Sciences (NIMHANS), Bangalore. Nine patients with SCA-12 (2 females) and 10 healthy controls (2 females) were included in the study. TMS was performed in all the subjects and various parameters such as resting motor threshold (RMT), central motor conduction time (CMCT) and contralateral silent period (cSP) were recorded. The left motor cortex was stimulated and the recording was done from right first dorsal interossei muscle. The severity of ataxia was assessed using the scale for assessment and rating in ataxia (SARA). ResultsThe mean age of the patients was 58.11 ± 7.56 years mean age at onset: 51.67 ± 4.18 years. The mean duration of illness was 9.44 ± 4.88 years. The mean SARA score was 13.83 ± 3.60. Patients with SCA-12 had significantly increased RMT (88.80 ± 12.78 %) compared to HC (44.90 ± 9.40 %, p < 0.05). A significantly prolonged CMCT was observed in patients (13.70 ± 2.52 msec) compared to HC (7.31 ± 1.21 msec, p < 0.05). In addition, cSP was significantly increased in SCA-12 patients (144.43 ± 25.79 msec) compared to HC (82.14 ± 28.90 msec, p < 0.05). ConclusionsPatients with SCA-12 demonstrate a reduced cortical excitability and increased cortical inhibition suggesting an increase in the GABAergic neurotransmission.

Subcellular localization and ER-mediated cytotoxic function of α1A and α1ACT in spinocerebellar ataxia type 6

Spinocerebellar ataxia type 6 (SCA6) is a polyglutamine (polyQ) disease, which is caused by the elongation of CAG repeats encoding polyQ in the CACNA1A gene. The CACNA1A gene encodes two proteins, namely, α1A (a subunit of the plasma membrane calcium channel), which is translated in its entire length, and α1ACT, which is translated from the second cistron, and both proteins have a polyQ tract. The α1A-polyQ and α1ACT-polyQ proteins with an elongated polyQ stretch have been reported to form aggregates in cells and induce neuronal cell death, but the subcellular localization of these proteins and their cytotoxic properties remain unclear. In this study, we first analyzed SCA6 model mice and found that α1A-polyQlong localized mainly to the Golgi apparatus, whereas a portion of α1ACT-polyQlong localized to the nucleus. Analysis using Neuro2a cells also showed similar subcellular localizations of these proteins, and a proportion of both proteins localized to the endoplasmic reticulum (ER). Cytotoxic studies demonstrated that both proteins induce both the ER stress response and apoptosis, indicating that they are able to induce ER stress-induced apoptosis.

On the Cut-Off Value of the Anteroposterior Diameter of the Midbrain Atrophy in Spinocerebellar Ataxia Type 2 Patients.

(1) Background: Spinocerebellar ataxias (SCA) is a term that refers to a group of hereditary ataxias, which are neurological diseases characterized by degeneration of the cells that constitute the cerebellum. Studies suggest that magnetic resonance imaging (MRI) supports diagnoses of ataxias, and linear measurements of the aneteroposterior diameter of the midbrain (ADM) have been investigated using MRI. These measurements correspond to studies in spinocerebellar ataxia type 2 (SCA2) patients and in healthy subjects. Our goal was to obtain the cut-off value for ADM atrophy in SCA2 patients. (2) Methods: This study evaluated 99 participants (66 SCA2 patients and 33 healthy controls). The sample was divided into estimations (80%) and validation (20%) samples. Using the estimation sample, we fitted a logistic model using the ADM and obtained the cut-off value through the inverse of regression. (3) Results: The optimal cut-off value of ADM was found to be 18.21 mm. The area under the curve (AUC) of the atrophy risk score was 0.957 (95% CI: 0.895-0.991). Using this cut-off on the validation sample, we found a sensitivity of 100.00% (95% CI: 76.84%-100.00%) and a specificity of 85.71% (95% CI: 42.13%-99.64%). (4) Conclusions: We obtained a cut-off value that has an excellent discriminatory capacity to identify SCA2 patients.

The Phenotypic Spectrum of Spinocerebellar Ataxia Type 19 in a Series of Latin American Patients.

Spinocerebellar ataxia 19 (SCA19) represents a rare autosomal dominant genetic disorder resulting in progressive ataxia and cerebellar atrophy. SCA19 is caused by variants in the KCND3 gene, which encodes a voltage-gated potassium channel subunit essential for cerebellar Purkinje cell function. We describe six cases from Chile and Mexico, representing the largest report on SCA19 in Latin America. These cases encompass a range of clinical presentations, highlighting the phenotypic variability within SCA19 from an early-onset, severe disease to a late-onset, slowly progressive condition with normal lifespan. While some patients present with pure ataxia, others also show cognitive impairment, dystonia, and other neurological symptoms. The correlations between specific KCND3 variants and phenotypic outcomes are complex and warrant further investigation. As the genomic landscape of spinocerebellar ataxias evolves, comprehensive genetic testing is becoming pivotal in improving diagnostic accuracy. This study contributes to a better understanding of the clinical spectrum of SCA19, laying the groundwork for further genotype-phenotype correlations and functional studies to elucidate the underlying pathophysiology.

Mild Deficits in Fear Learning: Evidence from Humans and Mice with Cerebellar Cortical Degeneration.

Functional brain imaging studies in humans suggest involvement of the cerebellum in fear conditioning but do not allow conclusions about the functional significance. The main aim of the present study was to examine whether patients with cerebellar degeneration show impaired fear conditioning and whether this is accompanied by alterations in cerebellar cortical activations. To this end, a 2 d differential fear conditioning study was conducted in 20 cerebellar patients and 21 control subjects using a 7 tesla (7 T) MRI system. Fear acquisition and extinction training were performed on day 1, followed by recall on day 2. Cerebellar patients learned to differentiate between the CS+ and CS-. Acquisition and consolidation of learned fear, however, was slowed. Additionally, extinction learning appeared to be delayed. The fMRI signal was reduced in relation to the prediction of the aversive stimulus and altered in relation to its unexpected omission. Similarly, mice with cerebellar cortical degeneration (spinocerebellar ataxia type 6, SCA6) were able to learn the fear association, but retrieval of fear memory was reduced. In sum, cerebellar cortical degeneration led to mild abnormalities in the acquisition of learned fear responses in both humans and mice, particularly manifesting postacquisition training. Future research is warranted to investigate the basis of altered fMRI signals related to fear learning.

Morphological changes of cerebral gray matter in spinocerebellar ataxia type 3 using fractal dimension analysis.

Spinocerebellar ataxia type 3 (SCA3), or Machado-Joseph disease, presents as a cerebellar cognitive affective syndrome (CCAS) and represents the predominant SCA genotype in Taiwan. Beyond cerebellar involvement, SCA3 patients exhibit cerebral atrophy. While prior neurodegenerative disease studies relied on voxel-based morphometry (VBM) for brain atrophy assessment, its qualitative nature limits individual and region-specific evaluations. To address this, we employed fractal dimension (FD) analysis to quantify cortical complexity changes in SCA3 patients. We examined 50 SCA3 patients and 50 age- and sex-matched healthy controls (HC), dividing MRI cerebral gray matter (GM) into 68 auto-anatomical subregions. Using three-dimensional FD analysis, we identified GM atrophy manifestations in SCA3 patients. Results revealed lateral atrophy symptoms in the left frontal, parietal, and occipital lobes, and fewer symptoms in the right hemisphere's parietal and occipital lobes. Focal areas of atrophy included regions previously identified in SCA3 studies, alongside additional regions with decreased FD values. Bilateral postcentral gyrus and inferior parietal gyrus exhibited pronounced atrophy, correlating with Scale for the Assessment and Rating of Ataxia (SARA) scores and disease duration. Notably, the most notable focal areas were the bilateral postcentral gyrus and the left superior temporal gyrus, serving as imaging biomarkers for SCA3. Our study enhances understanding of regional brain atrophy in SCA3, corroborating known clinical features while offering new insights into disease progression.

Brain Volumetric changes in patients with Spinocerebellar Ataxia Type 2

Aim: Spinocerebellar ataxia type 2 (SCA2) is a trinucleotide repeat disorder characterized by mutations in the ataxin-2 gene. Although the primary symptoms of this disease are related to cerebellar involvement, such as ataxia and dysarthria, cognitive disorders associated with supratentorial involvement, depression, and extrapyramidal symptoms are also common. The aim of this study was to investigate volumetric changes in patients with SCA2. Materials and Methods: Nine SCA2 patients and sixteen age and gender-matched healthy controls were included in the study. Voxel-based morphometry (VBM) was used to explore changes in whole brain gray and white matter, while surface-based morphometry (SBM) was employed to investigate changes in cortical thickness (CT), local gyrification index (LGI), sulcal depth (SD), and fractal dimension (FD). Deep learning methods were utilized for the automatic segmentation of subcortical gray matter structures and extrapyramidal system structures. Comparisons between groups were made using GLM, T-Test, and Mann-Whitney U test. Results: VBM results showed widespread gray matter loss in the cerebellum and widespread white matter loss in the brain stem (Cluster size: 25918 voxels for gray matter, 24557 voxels for white matter). SBM findings indicated a decrease in cortical thickness (Cluster size:19276 vertices for left hemisphere; 17276 vertices for right hemisphere), more pronounced in the supratentorial frontoparietal region, while FD, LGI, and SD did not differ between groups. Volume loss was observed in the subthalamic nucleus, globus pallidus internus and externus, and red nucleus in SCA2 patients. Conclusion: SCA2 patients exhibit white and gray matter volume loss in the infratentorial region. Additionally, they show a decrease in frontoparietal cortical thickness, while FD, LGI, and SD do not show any changes. Moreover, atrophy is also observed in the extrapyramidal system structures.

Drosophila melanogaster Neuromuscular Junction as a Model to Study Synaptopathies and Neuronal Autophagy.

Neuronal synapse dysfunction is a key characteristic of several neurodegenerative disorders, such as Alzheimer's disease, spinocerebellar ataxias, and Huntington's disease. Modeling these disorders to study synaptic dysfunction requires a robust and reproducible method for assaying the subtle changes associated with synaptopathies in terms of structure and function of the synapses. Drosophila melanogaster neuromuscular junctions (NMJs) serve as good models to study such alterations. Further, modifications in the microenvironment of synapses can sometimes reflect in the behavior of the animal, which can also be assayed in a high-throughput manner. The methods outlined in this chapter highlight assays to study the behavioral changes associated with synaptic dysfunction in a spinocerebellar ataxia type 3 (SCA3) model. Further, molecular assessment of alterations in NMJ structure and function is also summarized, followed by effects of autophagy pathway upregulation in providing neuroprotection. These methods can be further extended and modified to study the therapeutic effects of drugs or small molecules in providing neuroprotection for any synaptopathy models.

Step Width Estimation in Individuals With and Without Neurodegenerative Disease Via a Novel Data-Augmentation Deep Learning Model and Minimal Wearable Inertial Sensors.

Step width is vital for gait stability, postural balance control, and fall risk reduction. However, estimating step width typically requires either fixed cameras or a full kinematic body suit of wearable inertial measurement units (IMUs), both of which are often too expensive and time-consuming for clinical application. We thus propose a novel data-augmented deep learning model for estimating step width in individuals with and without neurodegenerative disease using a minimal set of wearable IMUs. Twelve patients with neurodegenerative, clinically diagnosed Spinocerebellar ataxia type 3 (SCA3) performed over ground walking trials, and seventeen healthy individuals performed treadmill walking trials at various speeds and gait modifications while wearing IMUs on each shank and the pelvis. Results demonstrated step width mean absolute errors of 3.3 ± 0.7cm and 2.9 ± 0.5cm for the neurodegenerative and healthy groups, respectively, which were below the minimal clinically important difference of 6.0cm. Step width variability mean absolute errors were 1.5cm and 0.8cm for neurodegenerative and healthy groups, respectively. Data augmentation significantly improved accuracy performance in the neurodegenerative group, likely because they exhibited larger variations in walking kinematics as compared with healthy subjects. These results could enable clinically meaningful and accurate portable step width monitoring for individuals with and without neurodegenerative disease, potentially enhancing rehabilitative training, assessment, and dynamic balance control in clinical and real-life settings.

Developing a pathway to clinical trials for CACNA1A-related epilepsies: A patient organization perspective.

CACNA1A-related disorders are rare neurodevelopmental disorders linked to variants in the CACNA1A gene. This gene encodes the α1 subunit of the P/Q-type calcium channel Cav2.1, which is globally expressed in the brain and crucial for fast synaptic neurotransmission. The broad spectrum of CACNA1A-related neurological disorders includes developmental and epileptic encephalopathies, familial hemiplegic migraine type 1, episodic ataxia type 2, spinocerebellar ataxia type 6, together with unclassified presentations with developmental delay, ataxia, intellectual disability, autism spectrum disorder, and language impairment. The severity of each disorder is also highly variable. The spectrum of CACNA1A-related seizures is broad across both loss-of-function and gain-of-function variants and includes absence seizures, focal seizures with altered consciousness, generalized tonic-clonic seizures, tonic seizures, status epilepticus, and infantile spasms. Furthermore, over half of CACNA1A-related epilepsies are refractory to current therapies. To date, almost 1700 CACNA1A variants have been reported in ClinVar, with over 400 listed as Pathogenic or Likely Pathogenic, but with limited-to-no clinical or functional data. Robust genotype-phenotype studies and impacts of variants on protein structure and function have also yet to be established. As a result, there are few definitive treatment options for CACNA1A-related epilepsies. The CACNA1A Foundation has set out to change the landscape of available and effective treatments and improve the quality of life for those living with CACNA1A-related disorders, including epilepsy. Established in March 2020, the Foundation has built a robust preclinical toolbox that includes patient-derived induced pluripotent stem cells and novel disease models, launched clinical trial readiness initiatives, and organized a global CACNA1A Research Network. This Research Network is currently composed of over 60 scientists and clinicians committed to collaborating to accelerate the path to CACNA1A-specific treatments and one day, a cure.

Efficiency of PGK1 proteins delivered to the brain via a liposomal system through intranasal route administration for the treatment of spinocerebellar ataxia type 3.

A patient-friendly and efficient treatment method for patients with spinocerebellar ataxia type 3 (SCA3) was provided through a nose-to-brain liposomal system. Initially, PGK1 was overexpressed in HEK 293-84Q-GFP diseased cells (HEK 293-84Q-GFP-PGK1 cells) to confirm its effect on the diseased protein polyQ. A decrease in polyQ expression was demonstrated in HEK 293-84Q-GFP-PGK1 cells compared to HEK 293-84Q-GFP parental cells. Subsequently, PGK1 was encapsulated in a liposomal system to evaluate its therapeutic efficiency in SCA3. The optimized liposomes exhibited a significantly enhanced positive charge, facilitating efficient intracellular protein delivery to the cells. The proteins were encapsulated within the liposomes using an optimized method involving a combination of heat shock and sonication. The liposomal system was further demonstrated to be deliverable to the brain via intranasal administration. PGK1/liposomes were intranasally delivered to SCA3 mice, which subsequently exhibited an amelioration of motor impairment, as assessed via the accelerated rotarod test. Additionally, fewer shrunken morphology Purkinje cells and a reduction in polyQ expression were observed in SCA3 mice that received PGK1/liposomes but not in the untreated, liposome-only, or PGK1-only groups. This study provides a non-invasive route for protein delivery and greater delivery efficiency via the liposomal system for treating neurodegenerative diseases.

Spinocerebellar ataxia type 2 has multiple ancestral origins

IntroductionSpinocerebellar ataxia type 2 (SCA2) is a dominant neurodegenerative disorder due to expansions of a CAG repeat tract (CAGexp) at the ATXN2 gene. Previous studies found only one ancestral haplotype worldwide, with a C allele at rs695871. This homogeneity was unexpected, given the severe anticipations related to SCA2. We aimed to describe informative ancestral haplotypes found in South American SCA2 families. MethodsSeventy-seven SCA2 index cases were recruited from Brazil, Peru, and Uruguay; 263 normal chromosomes were used as controls. The SNPs rs9300319, rs3809274, rs695871, rs1236900 and rs593226, and the STRs D12S1329, D12S1333, D12S1672 and D12S1332, were used to reconstruct haplotypes. ResultsEleven ancestral haplotypes were found in SCA2 families. The most frequent ones were A-G-C-C-C (46.7 % of families), G-C-C-C-C (24.6 %) and A-C-C-C-C (10.3 %) and their mean (sd) CAGexp were 41.68 (3.55), 40.42 (4.11) and 45.67 (9.70) (p = 0.055), respectively. In contrast, the mean (sd) CAG lengths at normal alleles grouped per haplotypes G-C-G-A-T, A-G-C-C-C and G-C-C-C-C were 22.97 (3.93), 23.85 (3.59), and 30.81 (4.27) (p < 0.001), respectively. The other SCA2 haplotypes were rare: among them, a G-C-G-A-T lineage was found, evidencing a G allele in rs695871. ConclusionWe identified several distinct ancestral haplotypes in SCA2 families, including an unexpected lineage with a G allele at rs695871, a variation never found in hundreds of SCA2 patients studied worldwide. SCA2 has multiple origins in South America, and more studies should be done in other regions of the world.

Cell-Free and In Vivo Characterization of the Inhibitory Activity of Lavado Cocoa Flavanols on the Amyloid Protein Ataxin-3: Toward New Approaches against Spinocerebellar Ataxia Type 3.

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder characterized by ataxia and other neurological manifestations, with a poor prognosis and a lack of effective therapies. The amyloid aggregation of the ataxin-3 protein is a hallmark of SCA3 and one of the main biochemical events prompting its onset, making it a prominent target for the development of preventive and therapeutic interventions. Here, we tested the efficacy of an aqueous Lavado cocoa extract and its polyphenolic components against ataxin-3 aggregation and neurotoxicity. The combination of biochemical assays and atomic force microscopy morphological analysis provided clear evidence of cocoa flavanols' ability to hinder ATX3 amyloid aggregation through direct physical interaction, as assessed by NMR spectroscopy. The chemical identity of the flavanols was investigated by ultraperformance liquid chromatography-high-resolution mass spectrometry. The use of the preclinical model Caenorhabditis elegans allowed us to demonstrate cocoa flavanols' ability to ameliorate ataxic phenotypes in vivo. To the best of our knowledge, Lavado cocoa is the first natural source whose extract is able to directly interfere with ATX3 aggregation, leading to the formation of off-pathway species.