Small molecule modulator of neuronal lysosome positioning and function resolves Alzheimers Disease-linked pathologies in cultured human neurons DOI Creative Commons

Amanda M. Snead,

Sruchi Patel,

Mia Krout

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 5, 2024

Abstract Abnormal increase in axonal lysosome abundance is associated with multiple neurodegenerative diseases including Alzheimer’s disease. However, the underlying mechanisms and disease relevance are not fully understood. We have recently identified RH1115 as a small molecule modulator of autophagy-lysosomal pathway that regulates positioning neurons. This allowed us to manipulate neuronal distribution axons interrogate its contribution both optimal functioning pathology. demonstrate only rescues aberrant buildup autophagic lysosomal intermediates but also reduces secreted Aβ42 levels human iPSC-derived neurons lacking adaptor, JIP3. thus restoring efficient transport has an anti-amyloidogenic effect promising therapeutic strategy for Furthermore, we show enhances degradation, requires adaptor JIP4 rescue pathology JIP3 KO increases JIP4-interacting membrane protein, TMEM55B. Lastly, treatment led striking locomotor defects zebrafish larvae. Thus, which can be impactful determined molecular targets modulating abundance.

Language: Английский

Small molecule modulator of neuronal lysosome positioning and function resolves Alzheimers Disease-linked pathologies in cultured human neurons DOI Creative Commons

Amanda M. Snead,

Sruchi Patel,

Mia Krout

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 5, 2024

Abstract Abnormal increase in axonal lysosome abundance is associated with multiple neurodegenerative diseases including Alzheimer’s disease. However, the underlying mechanisms and disease relevance are not fully understood. We have recently identified RH1115 as a small molecule modulator of autophagy-lysosomal pathway that regulates positioning neurons. This allowed us to manipulate neuronal distribution axons interrogate its contribution both optimal functioning pathology. demonstrate only rescues aberrant buildup autophagic lysosomal intermediates but also reduces secreted Aβ42 levels human iPSC-derived neurons lacking adaptor, JIP3. thus restoring efficient transport has an anti-amyloidogenic effect promising therapeutic strategy for Furthermore, we show enhances degradation, requires adaptor JIP4 rescue pathology JIP3 KO increases JIP4-interacting membrane protein, TMEM55B. Lastly, treatment led striking locomotor defects zebrafish larvae. Thus, which can be impactful determined molecular targets modulating abundance.

Language: Английский

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