Biology subjects

Dettmer, U.

Publications and source records attributed to Dettmer, U..

5 recordsLinked to original sources

bioRxiv2026

WDR44 drives de novo α-synuclein aggregation at the lysosomal membrane and promotes neuronal dysfunction in Parkinson's Disease

The aggregation of -synuclein (-SYN) into Lewy bodies (LBs) is a central event in the pathogenesis of Parkinsons disease (PD) and related synucleinopathies1,2. Despite significant advances in understanding -SYN self-assembly, the precise sequence of early aggregation steps has not been directly visualized in living neurons. Here, we use an optogenetic-induced protein aggregation system with a high temporal resolution to monitor the onset of -SYN assembly in neurons. We found that the initiation and accumulation of -SYN aggregates occur predominantly at the lysosomal membrane, an event driven by the -SYN N-terminus and modulated by the membrane-associated adaptor protein WD repeat-containing protein 44 (WDR44). Remarkably, we demonstrate that WDR44 knockdown markedly reduced de novo -SYN aggregation in both neuronal cultures and in vivo, whereas WDR44 overexpression enhances -SYN aggregation in PD patient-derived iPSC neurons. Consistent with its potential pathogenic involvement, WDR44 aberrantly accumulates in vivo and in the brains of PD patients, where it colocalizes with LB inclusions. Finally, we show that lysosome-associated -SYN aggregates compromised lysosomal structure and function, leading to neuronal impairment, a phenotype worsened by WDR44 overexpression, linking early aggregation events to downstream toxicity. Together, these findings reveal the earliest dynamic stages of -SYN oligomerization in living neurons and identify the WDR44--SYN interaction as a promising therapeutic target for reducing -SYN pathology and enabling early intervention in PD.

neuroscience↗

bioRxiv2025

Lipid droplets promote the aberrant liquid-liquid phase separation of alpha-synuclein leading to impaired energy homeostasis

Alpha-synuclein (Syn) inclusions, termed Lewy bodies, are the characteristic neuropathological feature of Parkinsons disease. Growing evidence points towards a role of aberrant liquid-liquid phase separation in the dysregulation of Syn and sequence of events that lead to the formation of Lewy bodies. However, the triggers leading to aberrant phase separation are unknown, as is the relevance of this phenomenon to the neurodegeneration process. In this study, we showed that Syn spontaneously phase separates into condensates in the presence of lipid droplets. These lipid droplet-rich condensates represent a toxic species of Syn that prevents the turnover of the entrapped lipid droplets; they are also toxic to neighbouring mitochondria which are depolarized and undergo increased mitophagy. These findings underscore the increasing importance of lipid droplets in the pathogenesis of neurodegenerative diseases, and Parkinsons disease in particular. The lipid droplets are significantly enriched within the neuromelanin in midbrain dopaminergic neurons in the substantia nigra and could therefore uniquely facilitate the early Syn-associated neurodegeneration of this region in PD. Our findings reveal a novel pathway implicated in the dysregulation of Syn that connects aberrant liquid-liquid phase separation, lipid droplets and mitochondrial toxicity.

neuroscience↗

bioRxiv2025

A Dual Assay to Compare Protein Levels and Toxicity of Alpha-Synuclein Variants: Acute Expression of Wild-Type versus S129A

Parkinsons disease (PD) affects over 12 million people worldwide and has the fastest-growing global impact. The pathological hallmark is the presence of Lewy bodies and Lewy neurites, which are intraneuronal lesions enriched in aggregated alpha-synuclein (S) that is typically hyper-phosphorylated at serine 129. Therefore, lowering phosphoserine 129 (pS129) may be a viable therapeutic strategy to treat PD. However, pS129 has also been proposed to regulate synaptic transmission and S degradation. In both cases, inhibiting pS129 could be detrimental. Here, we developed a sensitive assay in a human neuroblastoma model and utilized it to assess the relative expression levels and cytotoxicity of pS129 by comparing S wild-type (WT) vs. S129A (pS129-deficient). We show that the S129A mutant does not affect the acute expression levels or toxicity of S in a transient transfection paradigm. This provides new insight into the intricate interplay between S, phosphorylation, toxicity, and degradation. Our assay provides a versatile platform for understanding disease-relevant mechanisms and opens novel avenues for the design of future therapeutic interventions in PD and other -synucleinopathies.

cell biology↗

bioRxiv2024

Increased burden of rare risk variants across gene expression networks predisposes to sporadic Parkinson's disease

Alpha-synuclein (Syn) is an intrinsically disordered protein that accumulates in the brains of patients with Parkinsons disease and forms intraneuronal inclusions called Lewy Bodies. While the mechanism underlying the dysregulation of Syn in Parkinsons disease is unclear, it is thought that prionoid cell-to-cell propagation of Syn has an important role. Through a high throughput screen, we recently identified 38 genes whose knock down modulates Syn propagation. Follow up experiments were undertaken for two of those genes, TAX1BP1 and ADAMTS19, to study the mechanism with which they regulate Syn homeostasis. We used a recently developed M17D neuroblastoma cell line expressing triple mutant (E35K+E46K+E61K) "3K" Syn under doxycycline induction. 3K Syn spontaneously forms inclusions that show ultrastructural similarities to Lewy Bodies. Experiments using that cell line showed that TAX1BP1 and ADAMTS19 regulate how Syn interacts with lipids and phase separates into inclusions, respectively, adding to the growing body of evidence implicating those processes in Parkinsons disease. Through RNA sequencing, we identified several genes that are differentially expressed after knock-down of TAX1BP1 or ADAMTS19. Burden analysis revealed that those differentially expressed genes (DEGs) carry an increased frequency of rare risk variants in Parkinsons disease patients versus healthy controls, an effect that was independently replicated across two separate cohorts (GP2 and AMP-PD). Weighted gene co-expression network analysis (WGCNA) showed that the DEGs cluster within modules in regions of the brain that develop high degrees of Syn pathology (basal ganglia, cortex). We propose a novel model for the genetic architecture of sporadic Parkinsons disease: increased burden of risk variants across genetic networks dysregulates pathways underlying Syn homeostasis, thereby leading to pathology and neurodegeneration.

cell biology↗

bioRxiv2024

The Role of Alpha Synuclein in Synucleinopathy: Impact on Lipid Regulation at Mitochondria ER Membranes

The protein alpha-synuclein (Syn) plays a critical role in the pathogenesis of synucleinopathy, which includes Parkinsons disease and multiple system atrophy, and mounting evidence suggests that lipid dyshomeostasis is a critical phenotype in these neurodegenerative conditions. Previously, we identified that Syn localizes to mitochondria-associated endoplasmic reticulum membranes (MAMs), temporary functional domains containing proteins that regulate lipid metabolism, including the de novo synthesis of phosphatidylserine. In the present study, we have analyzed the lipid composition of postmortem human samples, focusing on the substantia nigra pars compacta of Parkinsons disease and controls, as well as three less affected brain regions of Parkinsons donors. To further assess synucleinopathy-related lipidome alterations, similar analyses were performed on the striatum of multiple system atrophy cases. Our data show 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 Parkinsons disease. Some of these alterations, albeit to a lesser degree, are also observed multiples system atrophy. Using induced pluripotent stem cell-derived neurons, we show that Syn contributes to regulating phosphatidylserine metabolism at MAM domains, and that Syn dosage parallels the perturbation in phosphatidylserine levels. Our results support the notion that Syn 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. Significance StatementSynucleinopathy is a complex group of neurodegenerative disorders whose causes and underlying mechanisms remain unknown. In this work, we examined synucleinopathy postmortem brain samples and patient-derived neuron models and identified the functional impairment of the mitochondrial-associated endoplasmic reticulum membrane (MAM) domain, which facilitates lipid regulation. The protein alpha-synuclein is associated with synucleinopathy and increasing levels result in the mislocalization of this protein and the disruption of MAM domains, which, in turn, results in lipid and membrane composition alterations. Specifically, we report that increased alpha-synuclein expression impairs the regulation of phosphatidylserine synthase 2 and the levels of phosphatidylserine in cellular membranes from affected cells. Our study offers mechanistic insight tying alpha-synuclein pathology and lipid dysregulation as seminal factors in synucleinopathy, which may have pathogenic and therapeutic implications.

neuroscience↗