The ordered assembly of α-synuclein protein encoded by SNCA into filaments characterizes neurodegenerative synucleinopathies. Lewy body disease (LBD) shows predominantly neuronal and multiple system atrophy (MSA), predominantly oligodendrocytic α-synuclein pathology affecting subcortical brain structures. Based on cryo-electron microscopy, it was reported that the structures of α-synuclein filaments from LBD differ from MSA and juvenile-onset synucleinopathy (JOS). The rare atypical MSA subtype shows abundant neuronal argyrophilic α-synuclein inclusions in the limbic system. Current concepts indicate that disease entities are characterized by unique protofilament folds. Here we demonstrate that α-synuclein can form a Lewy-MSA hybrid fold, leading to the atypical histopathological form of MSA. Distinct biochemical characteristics of α-synuclein, as demonstrated by protease-sensitivity digestion assay, seed amplification assays (SAAs), and conformational stability assays (CSA), are also linked to cytopathological differences. We expand the current structure-based classification of α-synucleinopathies and propose that cell-specific protein pathologies can be associated with distinct filament folds.
© 2025. The Author(s).

The expression level of α-synuclein is thought to play a crucial role in the pathogenesis of Parkinson's disease. However, little is known about the molecular mechanisms regulating the transcription of its gene, SNCA, particularly in the context of the disease. The transcription factor ZSCAN21 has been shown to act on SNCA, but whether ZSCAN21 is actually involved in the induction of SNCA transcription in Parkinson's disease is unknown. To address this question, we used the MPTP mouse model and LUHMES-derived dopaminergic neuronal spheroids, subjected to Parkinson's disease-related neurotoxins and mutations. We show that MPP+-treated spheroids recapitulate the main features of α-synuclein pathology and that MPP+-triggered transcriptional induction of SNCA is associated with ZSCAN21 stabilisation. Importantly, knock-down of ZSCAN21 prevents both the MPP+-triggered increase in α-synuclein mRNA and pre-mRNA levels in LUHMES-derived spheroids and the death of dopaminergic neurons in the substantia nigra of MPTP-treated mice. These effects are recapitulated by knockdown of TRIM17, a ZSCAN21 stabiliser which prevents its ubiquitination and degradation mediated by TRIM41. Moreover, reducing the interaction between ZSCAN21 and TRIM41, either by inserting Parkinson's disease-associated mutations into the TRIM41 gene or by preventing SUMOylation of ZSCAN21, results in both stabilisation of ZSCAN21 and induction of SNCA. Taken together, our data strongly suggest that ZSCAN21 is a crucial transcription factor for pathogenic α-synuclein expression and neurodegeneration in Parkinson's disease, pointing to its regulators, TRIM17 and TRIM41, as original therapeutic targets for a neuroprotective treatment of Parkinson's disease.
© 2025. The Author(s).

The protein alpha-synuclein (αSyn) plays a pivotal role in the pathogenesis of synucleinopathies, including Parkinson's disease and multiple system atrophy, with growing evidence indicating that lipid dyshomeostasis is a key phenotype in these neurodegenerative disorders. Previously, we identified that αSyn localizes, at least in part, to mitochondria-associated endoplasmic reticulum membranes (MAMs), which are transient functional domains containing proteins that regulate lipid metabolism, including the de novo synthesis of phosphatidylserine. In the present study, we analyzed the lipid composition of postmortem human samples, focusing on the substantia nigra pars compacta of Parkinson's disease and controls, as well as three less affected brain regions of Parkinson's donors. To further assess synucleinopathy-related lipidome alterations, similar analyses were performed on the striatum of multiple system atrophy cases. Our data reveal region- and disease-specific changes in the levels of lipid species. Specifically, our data revealed alterations in the levels of specific phosphatidylserine species in brain areas most affected in Parkinson's disease. Some of these alterations, albeit to a lesser degree, are also observed in multiple system atrophy. Using induced pluripotent stem cell-derived neurons, we show that αSyn regulates phosphatidylserine metabolism at MAM domains, and that αSyn dosage parallels the perturbation in phosphatidylserine levels. These findings support the notion that αSyn pathophysiology is linked to the dysregulation of lipid homeostasis, which may contribute to the vulnerability of specific brain regions in synucleinopathy. These findings have significant therapeutic implications.
© 2025. The Author(s).

The development of age-related neurodegenerative diseases is associated with the accumulation of damaged and misfolded proteins. Such proteins are eliminated from cells by proteolytic systems, mainly by 20S proteasomes, whose activity declines with age. Its stimulation has been recognized as a promising approach to delay the onset or ameliorate the symptoms of neurodegenerative disorders. Here we present peptidomimetics that are very effective in stimulating the proteasome in biochemical assays and in cell culture. They are stable in human plasma and capable of penetrating the cell membranes. The activators demonstrated the ability to enhance h20S degradation of α-synuclein and tau, whose aggregates are involved in the development of Parkinson's and Alzheimer's diseases, respectively. The peptidomimetics did not show cytotoxicity to HEK293T and primary hippocampal cells. Additionally, these compounds were highly effective in reducing the amount of phosphorylated α-synuclein aggregates in hippocampal neurons in a mouse embryonic cell model.

Accumulation of misfolded α-synuclein protein in intracellular inclusion bodies of dopaminergic neurons underlies the pathogenesis of Synucleinopathies, which include Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA). Therefore, clearance of misfolded α-synuclein from dopaminergic neurons could in principle offer a therapeutic window for Synucleinopathies, which currently remain untreatable. In this study, we employ the Affinity-directed PROtein Missile (AdPROM) system consisting of the substrate receptor of the CUL2-E3 ligase complex VHL and a nanobody selectively recognising the human α-synuclein protein and demonstrate targeted degradation of endogenous α-synuclein from human cell lines with remarkable selectivity. We further demonstrate that targeted degradation of α-synuclein prevents the pre-formed fibril (PFF)-induced aggregation of α-synuclein in primary neurons derived from rats expressing human α-synuclein. This approach represents the first demonstration of nanobody-guided proteasomal degradation of all clinically relevant α-synuclein variants, highlighting its potential as a therapeutic strategy against Synucleinopathies.