Alpha‐synuclein‐associated changes in PINK1‐PRKN‐mediated mitophagy are disease context dependent
Abstract
Alpha‐synuclein (αsyn) aggregates are pathological features of several neurodegenerative conditions including Parkinson disease (PD), dementia with Lewy bodies, and multiple system atrophy (MSA). Accumulating evidence suggests that mitochondrial dysfunction and impairments of the autophagic‐lysosomal system can contribute to the deposition of αsyn, which in turn may interfere with health and function of these organelles in a potentially vicious cycle. Here we investigated a potential convergence of αsyn with the PINK1‐PRKN‐mediated mitochondrial autophagy pathway in cell models, αsyn transgenic mice, and human autopsy brain. PINK1 and PRKN identify and selectively label damaged mitochondria with phosphorylated ubiquitin (pS65‐Ub) to mark them for degradation (mitophagy). We found that disease‐causing multiplications of αsyn resulted in accumulation of the ubiquitin ligase PRKN in cells. This effect could be normalized by starvation‐induced autophagy activation and by CRISPR/Cas9‐mediated αsyn knockout. Upon acute mitochondrial damage, the increased levels of PRKN protein contributed to an enhanced pS65‐Ub response. We further confirmed increased pS65‐Ub‐immunopositive signals in mouse brain with αsyn overexpression and in postmortem human disease brain. Of note, increased pS65‐Ub was associated with neuronal Lewy body‐type αsyn pathology, but not glial cytoplasmic inclusions of αsyn as seen in MSA. While our results add another layer of complexity to the crosstalk between αsyn and the PINK1‐PRKN pathway, distinct mechanisms may underlie in cells and brain tissue despite similar outcomes. Notwithstanding, our finding suggests that pS65‐Ub may be useful as a biomarker to discriminate different synucleinopathies and may serve as a potential therapeutic target for Lewy body disease.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 31, 2023
- Source ID
- 10.1111/bpa.13175
Entities
People
- Ayman H. Faroqi
- Dennis W. Dickson
- Fabienne C. Fiesel
- Guojun Bu
- Jenny M. Bredenberg
- Jonathan A. Carr
- Marion Delenclos
- Melissa E. Murray
- Owen A. Ross
- Pamela J. Mclean
- Shunsuke Koga
- Taylor Hsuan‐yu Chen
- Wolfdieter Springer
- Xu Hou
- Zbigniew K Wszolek
Organizations
- Alzheimer's Association
- Congressionally Directed Medical Research Programs
- Mayo Clinic
- Mayo Clinic Graduate School of Biomedical Sciences
- National Institute of Neurological Disorders and Stroke
- Stellenbosch University