Neuropathological and Molecular Features Associated With a Heterozygous DNAJC7 Mutation in Amyotrophic Lateral...

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with poorly understood molecular underpinnings.
• Heterozygous variants in DNAJC7, a cochaperone crucial for protein quality control, are implicated as potential ALS risk factors.
• The precise neuropathological impact of heterozygous DNAJC7 mutations remains unclear.

Purpose of the Study:

• To investigate the molecular and neuropathological consequences of a heterozygous DNAJC7 mutation in ALS.
• To clarify the role of DNAJC7 in the pathogenesis of ALS.

Main Methods:

• Genetic screening of 39 Japanese ALS patients identified a novel heterozygous frameshift mutation in DNAJC7.
• Biochemical and neuropathological analyses were conducted on postmortem tissues from the patient with the mutation, ALS cases without the mutation, and control cases.

Main Results:

• DNAJC7 mRNA and protein levels were elevated in ALS cases without the mutation compared to controls.
• The patient with the DNAJC7 mutation exhibited lower DNAJC7 mRNA and protein levels, suggesting an attenuated protective response.
• DNAJC7 partially colocalized with phospho-TDP-43 inclusions, indicating a role in modulating TDP-43 aggregation.

Conclusions:

• Neuropathological evidence links heterozygous DNAJC7 mutation to ALS, characterized by impaired protein expression.
• A loss-of-function mechanism in DNAJC7 compromises protective responses to TDP-43 pathology in ALS.
• DNAJC7 emerges as a potential key modulator and therapeutic target in ALS pathogenesis.