TY  - JOUR
AU  - Flores-León, Manuel
AU  - Outeiro, Tiago F
TI  - Expanding our understanding of synucleinopathies: proteinopathy, proteinopenia, and lipidopathy.
JO  - The FEBS journal
VL  - 292
IS  - 18
SN  - 0014-2956
CY  - Oxford [u.a.]
PB  - Wiley-Blackwell
M1  - DZNE-2025-01098
SP  - 4774 - 4788
PY  - 2025
AB  - A possible consequence of the process of protein aggregation in neurodegenerative diseases is the depletion of soluble protein species (proteinopenia), which may, at least in some cases, reduce protein function/activity. This concept, which is often overlooked, may play a role in synucleinopathies such as Parkinson's disease (PD), and dementia with Lewy bodies (DLB), where the protein α-synuclein (aSyn) is known to accumulate in insoluble inclusions. aSyn is at the crossroads between cellular proteostasis and lipidostasis networks and, therefore, we must be aware of the complexity we face when we try to understand the molecular basis of synucleinopathies. Importantly, aSyn and β-glucocerebrosidase (GCase), a sphingolipid hydrolase also strongly implicated in PD and DLB, are connected to lipid biology and to protein quality control function. Thus, changes in the normal relationship between these two proteins may shift the balance in the cell and lead to proteinopathy and/or proteinopenia, while also affecting lipidostasis of cells in the brain. Thus, pathological mechanisms that are a consequence of (a) loss-of-function, (b) gain-of-toxic function, and (c) alterations in lipidostasis need to be carefully analyzed and integrated in our study of the molecular underpinnings of neurodegenerative mechanisms. Here, we highlight implications of the depletion of the soluble form of aSyn, and of GCase, and discuss how state-of-the-art 'omics technologies' could be deployed to assist in the clinical assessment of synucleinopathies.
KW  - Humans
KW  - alpha-Synuclein: metabolism
KW  - alpha-Synuclein: genetics
KW  - Synucleinopathies: metabolism
KW  - Synucleinopathies: pathology
KW  - Synucleinopathies: genetics
KW  - Parkinson Disease: metabolism
KW  - Parkinson Disease: pathology
KW  - Parkinson Disease: genetics
KW  - Glucosylceramidase: genetics
KW  - Glucosylceramidase: metabolism
KW  - Lipid Metabolism
KW  - Animals
KW  - Proteostasis: genetics
KW  - Lewy Body Disease: metabolism
KW  - Lewy Body Disease: pathology
KW  - Lewy Body Disease: genetics
KW  - Parkinson's disease (Other)
KW  - alpha‐synuclein (Other)
KW  - lipids (Other)
KW  - protein aggregation (Other)
KW  - synucleinopathy (Other)
KW  - transcription (Other)
KW  - alpha-Synuclein (NLM Chemicals)
KW  - Glucosylceramidase (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39996490
C2  - pmc:PMC12443472
DO  - DOI:10.1111/febs.70011
UR  - https://pub.dzne.de/record/281351
ER  -