ALS/FTD-associated protein FUS induces mitochondrial dysfunction by preferentially sequestering respiratory chain...

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Dysregulation of the FUS protein is implicated in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).
• Toxic gain of function of FUS, through mutations or overexpression, disrupts cellular processes, including mitochondrial function.

Purpose of the Study:

• To investigate the mechanisms by which FUS dysregulation leads to mitochondrial dysfunction in ALS/FTD.
• To identify the specific cellular targets of FUS in the context of ALS/FTD pathogenesis.

Main Methods:

• Overexpression of wild-type and mutant FUS in human cells.
• Analysis of FUS association with mRNAs and proteins.
• Assessment of mitochondrial network organization, aerobic respiration, and reactive oxygen species production.
• Examination of FUS binding to mitochondrial-encoded mRNAs.
• Analysis of patient-derived fibroblasts with FUS mutations.

Main Results:

• FUS overexpression leads to sequestration of mRNAs encoding mitochondrial respiratory chain components.
• This sequestration reduces protein levels, causing disorganized mitochondria, impaired respiration, and increased reactive oxygen species.
• Mutant FUS associates with mitochondria and mitochondrial-encoded mRNAs.
• Similar mitochondrial defects were observed in ALS patient fibroblasts with FUS mutations.
• FUS loss of function does not cause these mitochondrial defects.

Conclusions:

• Respiratory chain complex mRNA sequestration by FUS is a key mechanism underlying mitochondrial defects in ALS/FTD.
• This sequestration contributes to the toxic gain of function of FUS in the disease spectrum.
• The findings provide novel insights into the pathogenesis of FUS-linked ALS/FTD.