Parkin beyond Parkinson’s Disease—A Functional Meaning of Parkin Downregulation in TDP-43 Proteinopathies

Abstract

Parkin and PINK1 are key regulators of mitophagy, an autophagic pathway for selective elimination of dysfunctional mitochondria. To this date, parkin depletion has been associated with recessive early onset Parkinson’s disease (PD) caused by loss-of-function mutations in the PARK2 gene, while, in sporadic PD, the activity and abundance of this protein can be compromised by stress-related modifications. Intriguingly, research in recent years has shown that parkin depletion is not limited to PD but is also observed in other neurodegenerative diseases—especially those characterized by TDP-43 proteinopathies, such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here, we discuss the evidence of parkin downregulation in these disease phenotypes, its emerging connections with TDP-43, and its possible functional implications.

Frequency of Parkinson’s Disease Genes and Role of PARK2 in Amyotrophic Lateral Sclerosis: An NGS Study

“…Homozygous mutations in PARK2 and PINK1 are the most known causes of autosomal recessive early onset parkinsonism [ 13 , 34 ]. Furthermore, single heterozygous PARK2 or PINK1 variants are higher in PD patients than controls and have been associated with subclinical parkinsonism [ 35 ]. PARK2 and PINK1 are essential regulators of mitophagy, one of the autophagy pathways for selective removal of dysfunctional mitochondria.…”

“…Intriguingly, recent research has shown that parkin depletion is not limited to PD but is also observed in other neurodegenerative diseases, especially those characterized by TDP-43 proteinopathies, such as ALS and frontotemporal lobar degeneration [ 35 ]. In particular, decreased levels of parkin have been found in mouse adult brain, stem-cell-derived human neurons, human fibroblasts, and motor neurons from sporadic ALS patients [ 35 ]. Furthermore, in motor neurons derived from sporadic ALS patients, a correlation has been established between decreased parkin and the presence of TDP-43 aggregates [ 37 ].…”

Mitochondrial‐derived vesicles: Recent insights

“…Such a defective process occurs in Parkinson's disease 10 and is due to the mutations of the corresponding genes. Recent reports demonstrate that the recessive early‐onset Parkinson's disease is associated with biallelic mutations in PINK1 43 and the loss‐of‐function mutations in the PARK2 gene, resulting in Parkin depletion 44 . In Parkin‐deficient mice, mutations in the mouse Parkin gene (Park2) are accomplished by the targeted deletion of Parkin exon 2 45 …”

“…Recent reports demonstrate that the recessive early-onset Parkinson's disease is associated with biallelic mutations in PINK1 43 and the loss-of-function mutations in the PARK2 gene, resulting in Parkin depletion. 44 In Parkin-deficient mice, mutations in the mouse Parkin gene (Park2) are accomplished by the targeted deletion of Parkin exon 2. 45 Recent studies uncovered both the proteins beyond the MDVs flux to lysosomes/endo-lysosomal compartment and those required for the fusion between the MDVs (containing oxidized proteins and lipids) and the degradative organelle.…”

The Role of Ubiquitin in Regulating Stress Granule Dynamics

“…The E3 ubiquitin ligase Parkin has been reported to ubiquitinate TDP-43 and to facilitate its cytoplasmic accumulation in a multiprotein complex containing HDAC6 ( Hebron et al, 2013 ). Moreover, TDP-43 was shown to regulate Parkin expression, resulting in a decreased abundance of Parkin in motor neurons from ALS patients with TDP-43 pathology, which may contribute to the mitochondrial defects observed in TDP-43 pathologies ( Polymenidou et al, 2011 ; Lagier-Tourenne et al, 2012 ; Gaweda-Walerych et al, 2021 ). The E2 ubiquitin conjugating enzymes UBE2E and the ubiquitin isopeptidase Y (UBPY) were identified as TDP-43-interacting proteins that regulate the ubiquitination of wildtype TDP-43, TDP-43 mutants and C-terminal fragments ( Hans et al, 2014 ).…”