Analysis of Brain and Cerebrospinal Fluid from Mouse Models of the Three Major Forms of Neuronal Ceroid Lipofuscinosis Reveals Changes in the Lysosomal Proteome

Proteomic and functional analyses in disease models reveal CLN5 protein involvement in mitochondrial dysfunction

“…An implication of mitochondrial dysfunction and TCA cycle II has previously been reported in a proteomic study of pre-symptomatic thalami in Ppt1 −/− mice 12 . Moreover, comparing our dataset with ones generated by previous proteomic studies 12,14,46 , a considerable overlap between mtDEPs identified in Ppt1 −/− , Tpp1 −/− mouse studies, and CLN3/CLN5 interaction partners has been identified ( Supplementary Table S4). Shared mitochondrial carriers (MDH2, PITRM1, SLC25A3, SPNS1), proteins implicated in apoptotic (CARL, CLIC4, YWHAQ) and metabolic processes (AK2, DLST, ECI1, HKDC1, GANAB), astrocyte development (VIM), mitochondrial organization (CHCHD3, VAT1) and energy production (NDUFV2, ENO1) further reinforces the hypothesis of a common molecular theme 14,47,48 and neuronal impairment in NCLs (Fig.…”

Urine proteomics analysis of patients with neuronal ceroid lipofuscinoses

“…Phosphatidylethanolamine-binding protein 1 (PEBP1) is a protease inhibitor with multiple functions; why it is increased in CLN2 is unknown. GALNS N-acetylgalactosamine-6-sulfatase and beta-hexosaminidase alpha are part of the glycosaminoglycan degradation pathway, which has been previously implicated in NCL disease ( Sleat et al., 2019 ).…”

“…Mast cell activity has not been specifically assessed in NCL, but mast cells have been observed to surround the optic nerve in a mouse model for CLN3 disease indicating compromise of the blood-brain barrier ( Sappington et al., 2003 ). Proteomic analysis of CLN1 and CLN2 mouse model brain tissue has shown increased levels of CD63 ( Sleat et al., 2019 ), which is thought to play a role in activation of mast cells and basophils ( Kabashima et al., 2018 ). Therefore it is possible that the presence of HEXA is indicative of a mast cell-associated immune response in NCL.…”

“…Proteins of interest identified from the phase 1 profiling analysis are considered as potential biomarker candidates for corresponding CLN2, CLN5, and CLN6 diseases in human patients. As additional biomarkers can be included we also selected peptides from other biomarker candidates described in previous NCL omics studies ( Sleat et al., 2017 , 2019 ) to confirm these in our analyses. Using the targeted multiplex assay we applied this to a larger separate cohort of CLN2 disease patient samples and patient samples with CLN5 and CLN6 disease to confirm phase 1 findings.…”

Neuroinflammation and progressive myoclonus epilepsies: from basic science to therapeutic opportunities

“…Recently, a proteomic analysis of brain and cerebrospinal fluid from Cln1- / - , Cln2- / - (lacking the 61 kDa lysosomal tripeptidyl peptidase 1, Tpp1; OMIM #204500) and Cln3- / - mouse models have revealed an upregulation in the levels of (i) proteins related to lysosomal function (Arsa, CD63, Ctsa, Ctsd, Ctsz, Hexb, Fuca1 and Gns); (ii) inflammatory response (GPNMB, CD44, LYZ2, SERPINA3N, GFAP, AIF1/IBA1, APOE, Capg, Cpne1, Gbp2, Ifit3, Irgm1, itgb2 and Stat1) and (iii) complement proteins (C1qa, C1qb, C1qc, C4b, CD44 and S100A6) (Ref. 49). All these data suggest that glial-derived neuroinflammation could underlie the pathophysiology of the NCLs.…”