This paper is still a preprint.

ATH has not published much about mitochondria, but it presented "a Kosman poster" about how ATH434 protects mitochondria through a strong antioxidant effect last autumn. It looks like Kosman had plans to study this antioxidant effect "on the lipid peroxidation downstream of ROS" as Kosman tells on the poster. So, this is most likely how ATH434 works on the lipids on the mitochondria level.

This new paper confirms that lipid (peroxidation?) in mitochondria is the problem in PD and MSA.

bioRxiv

[Preprint]. 2024 Jun 17:2024.06.17.599406.

doi: 10.1101/2024.06.17.599406.

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

Peter A Barbuti, Cristina Guardia-Laguarta, Taekyung Yun, Zena K Chatila, Xena Flowers, Bruno Fr Santos, Simone B Larsen, Nobutaka Hattori, Elizabeth Bradshaw, Ulf Dettmer, Saranna Fanning, Manon Vilas, Hasini Reddy, Andrew F Teich, Rejko Krüger, Estela Area-Gomez, Serge Przedborski

• PMID: 38948777

PMCID: PMC11212931 DOI: 10.1101/2024.06.17.599406

Abstract

The protein alpha-synuclein (αSyn) plays a critical role in the pathogenesis of synucleinopathy, which includes Parkinson's disease and multiple system atrophy, and mounting evidence suggests that lipid dyshomeostasis is a critical phenotype in these neurodegenerative conditions. Previously, we identified that αSyn 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 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 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 Parkinson's 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 αSyn contributes to regulating phosphatidylserine metabolism at MAM domains, and that αSyn dosage parallels the perturbation in phosphatidylserine levels. Our results 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.

Significance statement: Synucleinopathy 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.