Transmembrane Batten Disease Proteins Interact With a Shared Network of Vesicle Sorting Proteins, Impacting Their Synaptic Enrichment

Abstract

Batten disease is unique among lysosomal storage disorders for the early and profound manifestation in the central nervous system, but little is known regarding potential neuron-specific roles for the disease-associated proteins. We demonstrate substantial overlap in the protein interactomes of three transmembrane Batten proteins (CLN3, CLN6, and CLN8), and that their absence leads to synaptic depletion of key partners (i.e., SNAREs and tethers) and altered synaptic SNARE complexing in vivo, demonstrating a novel shared etiology.

Cellular Modeling of CLN6 with IPSC-derived Neurons and Glia

“…Further bulk-transcriptomic analyses identified variations in the transcriptional expression of numerous gene pathways involved in axonal, synaptic, and neuronal apoptotic processes. Interestingly, many of these transcriptional changes were correlated with shifts in transcript and protein expression that had been identified in other models of NCL and lysosomal disease (Gomez-Giro et al, 2019;Pérez-Brangulí et al, 2014;Rechtzigel et al, 2022;Sun et al, 2000). These data indicate that our CLN6-IPSCs and their derivatives can serve as appropriate human cellular models for the CLN6.…”

“…Clinical features include progressive cognitive and motor decline, seizures, blindness, and an early death (Cárcel-Trullols et al, 2015; Haltia and Goebel, 2013), while pathological features include intracellular accumulation of lipid/proteolipid storage material. The genes/proteins involved in NCLs intersect with their involvement in the endolysosomal system and include catabolic lysosomal acid hydrolases (LAHs; CLN1, CLN2, CLN10, CLN13) along with several membrane-bound proteins involved in trafficking or other non-catabolic functions (CLN5, CLN6, CLN8)(Rechtzigel et al, 2022). Neuronal ceroid lipofuscinosis, type 6 (CLN6) is caused by bi-allelic pathogenic variants in the CLN6 gene, which encodes a ubiquitously-expressed resident endoplasmic reticulum (ER) protein (CLN6p, Uniprot # Q9NWW5), which is involved in trafficking lysosomal proteins from the ER to the Golgi and eventual delivery to lysosomes (Bajaj et al, 2020; Gao et al, 2002).…”

Longitudinal Deep Multi-Omics Profiling in aCLN3Δex7/8Minipig Model Reveals Novel Biomarker Signatures for Batten Disease

“…The absence of functional CLN3 gives rise to an intricate disease state commonly referred to as Batten disease. Cells lacking functional CLN3 protein exhibit a wide range of abnormalities including trafficking deficits within the secretory pathway, changes in lipid composition, impaired autophagy, and altered lysosomal composition and function [26][27][28][29] . At the tissue level, the central nervous system is progressively impaired by extensive neuroinflammation 30 , while there is some evidence of progressive dysfunction in the heart, skeletal muscles, and immune cell populations in the periphery 31 .…”

Early postnatal administration of an AAV9 gene therapy is safe and efficacious in CLN3 disease

“…CLN3 is known to localize to the lysosome and is necessary for efficient lysosomal function, but its precise molecular functions are unknown (Jarvela et al, 1999). Some lines of evidence suggest CLN3 may have unique roles in neurons, which are the primary cells affected in the disease (Rechtzigel et al, 2022). Disease causing mutations disrupt the trafficking of CLN3 into neuronal processes, where it colocalizes with synaptic markers (Jarvela et al, 1999;Luiro et al, 2001).…”