Converging links between adult-onset neurodegenerative Alzheimer’s disease and early life neurodegenerative neuronal ceroid lipofuscinosis?

Abstract

Evidence from genetics and from analyzing cellular and animal models have converged to suggest links between neurodegenerative disorders of early and late life. Here, we summarize emerging links between the most common late life neurodegenerative disease, Alzheimer’s disease, and the most common early life neurodegenerative diseases, neuronal ceroid lipofuscinoses. Genetic studies reported an overlap of clinically diagnosed Alzheimer’s disease and mutations in genes known to cause neuronal ceroid lipofuscinoses. Accumulating data strongly suggest dysfunction of intracellular trafficking mechanisms and the autophagy-endolysosome system in both types of neurodegenerative disorders. This suggests shared cytopathological processes underlying these different types of neurodegenerative diseases. A better understanding of the common mechanisms underlying the different diseases is important as this might lead to the identification of novel targets for therapeutic concepts, the transfer of therapeutic strategies from one disease to the other and therapeutic approaches tailored to patients with specific mutations. Here, we review dysfunctions of the endolysosomal autophagy pathway in Alzheimer’s disease and neuronal ceroid lipofuscinoses and summarize emerging etiologic and genetic overlaps.

Recent insights into the networking of CLN genes and proteins in mammalian cells

“…Furthermore, efforts are being made to explore the repurposing of drugs for NCL and identifying biomarkers for monitoring disease progression and the patient response to therapy (Huber, 2021; Soldati et al, 2021). Intriguingly, there is significant genetic and pathological overlap of NCL with other forms of neurodegeneration including Alzheimer's disease, Parkinson's disease, frontotemporal dementia (FTD), and Tay‐Sachs disease, with several CLN proteins linked to those diseases (Figure 1) (Arrant et al, 2018; Chen et al, 2018; Klein & Hermey, 2023; Qureshi et al, 2020). Thus, the development of new therapies for the NCLs could also be highly beneficial for people affected by other forms of neurodegeneration.…”