PXD041888-1

PXD041888 is an original dataset announced via ProteomeXchange.

Title	Brain cell type specific proteomics approach to discover pathological mechanisms in the childhood CNS disorder mucolipidosis type IV
Description	1 Mucolipidosis IV (MLIV) is an ultra-rare, recessively inherited lysosomal disorder resulting from inactivating mutations in MCOLN1, the gene encoding the lysosomal cation channel TRPML1. The disease primarily affects the central nervous system (CNS), and manifests in the first year with cognitive and motor developmental delay, followed by a gradual decline in neurological function across the second decade of life, blindness and premature death in third or fourth decades. Brain pathology manifestations in MLIV are consistent with hypomyelinating leukodystrophy with brain iron accumulation. Presently there are no approved or investigational therapies for MLIV and pathogenic mechanisms remain largely unknown. MLIV mouse model, Mcoln1-/- mice, recapitulate all major manifestations of the human disease. Here, to better understand brain pathological mechanisms of the disease, we performed cell type specific MS/MS proteomics analysis in MLIV mouse model and reconstituted molecular signatures of the disease in freshly isolated populations of neurons, astrocytes, oligodendrocytes and neural stem cells or whole tissue cortical homogenates from young adult symptomatic Mcoln1-/- mice. Our analysis confirmed on molecular level major histopathological hallmarks of MLIV, such as hypomyelination, lysosomal dysregulation, impaired metabolism of lipids and polysaccharides, universally present in Mcoln1-/- tissue and brain cells. Importantly, pathway analysis in brain cell datasets revealed mitochondria-related alterations in all Mcoln1-/- brain cells expect oligodendrocytes, that was not possible to resolve in whole tissue data set. We also report unique proteome signatures and dysregulated pathways for each brain cell population used in this study. These data shed new light on cell-intrinsic mechanisms of MLIV and provide new insights for biomarker discovery and validation to advance translational studies for this disease
HostingRepository	MassIVE
AnnounceDate	2023-07-21
AnnouncementXML	Submission_2023-07-21_14:57:08.181.xml
DigitalObjectIdentifier
ReviewLevel	Non peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Bogdan Budnik
SpeciesList	scientific name: Mus musculus; common name: house mouse; NCBI TaxID: 10090;
ModificationList	Carbamidomethyl; TMTpro; Oxidation
Instrument	instrument model

Revision	Datetime	Status	ChangeLog Entry
0	2023-04-29 16:45:27	ID requested
⏵ 1	2023-07-21 14:57:08	announced

no publication

submitter keyword: lysosomal disease, mucolipidosis, TRPML1, central nervous system, brain cells, cell specific proteomics, biomarkers

Bogdan Budnik
contact affiliation	Wyss Institute, Harvard University
contact email	Bogdan.Budnik@wyss.harvard.edu
lab head
Bogdan Budnik
contact affiliation	Harvard University
contact email	Bogdan.Budnik@wyss.harvard.edu
dataset submitter

MassIVE dataset URI

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