Distinct multilevel misregulations of Parkin and PINK1 revealed in cell and animal models of TDP-43 proteinopathy

Cell Death & Disease, 2018 · DOI: 10.1038/s41419-018-1022-y · Published: September 3, 2018

Simple Explanation

This study investigates the roles of Parkin and PINK1, which are important for mitochondrial health, in the context of TDP-43 proteinopathy, a condition associated with ALS. The researchers found that TDP-43 accumulation leads to different problems with Parkin and PINK1 function. Specifically, TDP-43 reduces the amount of Parkin by affecting its RNA, even in ways that don't depend on the usual signals in the RNA. Unlike Parkin, TDP-43 doesn't change the amount of PINK1 RNA. Instead, it causes a buildup of a specific form of PINK1 in the cell because it interferes with the cell's protein disposal system. Experiments in fruit flies showed that increasing Parkin or decreasing PINK1 could counteract the harmful effects of TDP-43. This suggests that Parkin and PINK1 are part of a common pathway that goes wrong in TDP-43 proteinopathy, but in different ways.

Study Duration

Not specified

Participants

Knock-in flies, mouse primary neurons, and TDP-43Q331K transgenic mice

Evidence Level

Not specified

Key Findings

1
TDP-43 overexpression reduces Parkin mRNA levels through both intron-dependent and intron-independent mechanisms.
2
TDP-43 overexpression leads to cytosolic accumulation of cleaved PINK1 due to impaired proteasomal activity.
3
Upregulation of Parkin and downregulation of PINK1 improve the degenerative phenotypes in a Drosophila model of TDP-43 proteinopathy.

Research Summary

This study reveals that Parkin and PINK1 are differentially misregulated in TDP-43 proteinopathy at both RNA and protein levels. TDP-43 downregulates Parkin mRNA via an intron-independent mechanism requiring the RNA-binding and protein-protein interaction functions of TDP-43. Excess TDP-43 causes cytosolic accumulation of cleaved PINK1 due to impaired proteasomal activity, compromising mitochondrial functions.

Practical Implications

Therapeutic Strategies

The findings suggest that differential therapeutic strategies need to be developed when considering the Parkin–PINK1 pathway as a common target for treating ALS.

Understanding ALS Pathogenesis

Highlighting the complexity of ALS, the research emphasizes the importance of understanding the diverse mechanisms that contribute to the disease.

Targeting Mitochondrial Dysfunction

The study reinforces the importance of targeting mitochondrial dysfunction in ALS, particularly through modulation of the Parkin-PINK1 pathway.

Study Limitations

1
The exact mechanism of the intron/UTR-independent regulation of Parkin mRNA is yet to be unraveled.
2
Correcting the misregulations of Parkin or PINK1 only partially rescued the phenotypes of hTDP-43 ﬂies, suggesting involvement of other targets.
3
The in vitro assay showed only a small reduction of proteasomal activity by TDP-43 overexpression.

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