MINI REVIEW article
Front. Mol. Neurosci.
Sec. Brain Disease Mechanisms
Volume 18 - 2025 | doi: 10.3389/fnmol.2025.1681079
This article is part of the Research TopicProteostasis disruption in neurodegenerative disorders: Mechanisms and treatment strategiesView all 5 articles
Proteostasis Disruption and Lipid Dyshomeostasis in Neurodegeneration: Exploring Common Druggable Targets Across Sporadic and Monogenic Disorders
Provisionally accepted
Priscila Pereira Sena1*
Lea Friedrich1
Alcibiades Elias Villarreal2,3
Florian Fath1,4,5
Liubovi Sopco6
Mar Hernandez6
Maria Luiza Saraiva-Pereira7,8
Gabrielle Britton2,3
Jonasz Jeremiasz Weber1,5
Thorsten Schmidt1- 1Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
- 2Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT-AIP), Building 208, Ciudad del Saber, Clayton, Panama City, Panama
- 3Sistema Nacional de Investigación (SNI) in Panama, Secretaría Nacional de Ciencia Tecnología e Innovación (SENACYT), Panama City, Panama
- 4Department of Neurology, Huntington-Center NRW, St. Josef-Hospital Bochum, Ruhr University Bochum, Bochum, Germany
- 5Department of Human Genetics, Ruhr University Bochum, Bochum, Germany
- 6Neurovascular Research Laboratory, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain
- 7Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
- 8Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
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Neurodegenerative disorders pose an increasing burden in the aging society. These conditions share several molecular pathomechanisms, some of which may offer opportunities for therapeutic intervention. In this review, we explore a representative selection of sporadic and hereditary neurodegenerative diseases - namely Alzheimer's disease, cerebral amyloid angiopathy, and the polyQ disorders spinocerebellar ataxia types 2 and 3, as well as Huntington's disease - which all feature the accumulation of intra-or extracellular protein deposits as a hallmark. We place particular emphasis on dysregulations in proteostasis — underlying the formation of these aggregates — and the less commonly addressed disturbances in lipid metabolism. By highlighting potential mechanistic links across different classes of neurodegenerative diseases, we aim to provide new insights that may guide the identification of shared druggable targets and the development of broad-spectrum therapeutic strategies.
Keywords: Apolipoprotein E, APOE, aggregates, Autophagy, amyloid β, Cholesterol, plaques, polyglutamine
Received: 06 Aug 2025; Accepted: 29 Sep 2025.
Copyright: © 2025 Pereira Sena, Friedrich, Villarreal, Fath, Sopco, Hernandez, Saraiva-Pereira, Britton, Weber and Schmidt. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Priscila Pereira Sena, priscila.sena@med.uni-tuebingen.de
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