PXD024945

PXD024945 is an original dataset announced via ProteomeXchange.

Title	LC-MS/MS of SCA3 knock-in mouse cortex, cerebellum, and axons
Description	Spinocerebellar ataxia type 3 (SCA3/MJD) has a polyQ etiology but, the current knowledge on molecular processes and proteins involved in pathogenesis is insufficient. Due to its proteolytic function, Ataxin-3 can influence other proteins, yet the global picture of crucial proteins and pathways in SCA3 was not investigated previously. Here, we explored molecular SCA3 mechanism by interdisciplinary research paradigm combining SCA3 knock-in model, behavior, MRI, brain proteomics, precise axonal proteomics, neuronal energy recordings, labeling of vesicles, and inclusions and focusing in axonal compartment. Using the global proteomics, we found dysregulation of protein homeostasis over the entire disease progression. The early SCA3 phase was associated with reduced body weight gain, the presence of the number of dysregulated proteins related to metabolism and mitochondria, and an altered profile of oxygen consumption rate in neurons. Moreover, the early phase presented alterations of protein metabolism, cytoskeletal architecture, axonal and synaptic proteins. Protein dysregulations indicated that the compartment involved in SCA3 pathogenesis next to the mitochondria are also neuronal processes and axons in particular. To confirm that the axon is one of the central compartments in SCA3 pathogenesis, we performed targeted proteomics on axons and somatodendritic compartments. We revealed highly increased axonal localization of protein synthesis machinery, including ribosomes, translation factors, and RNA binding proteins, while the level of proteins responsible for cellular transport and mitochondria was decreased. In summary, the SCA3 disease mechanism is based on the broad influence of mutant ataxin-3 on the neuronal proteome. Processes central in our SCA3 model include disturbed localization of proteins between axonal and somatodendritic compartment, early neuronal energy deficit, altered neuronal cytoskeletal structure, an overabundance of protein synthetic machinery in axons.
HostingRepository	PRIDE
AnnounceDate	2021-04-08
AnnouncementXML	Submission_2021-04-07_23:48:47.992.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Lukasz Marczak
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2021-03-23 03:40:44	ID requested
⏵ 1	2021-04-07 23:48:48	announced

Dataset with its publication pending

submitter keyword: ataxin-3, mouse, knock-in, knockin, SCA3, MJD, ataxia, spinocerebellar, CAG, polyQ, neurodegenerative, proteome, LC-MS/MS, brain, cerebral cortex, cerebellum, axon

Lukasz Marczak
contact affiliation	Institute of Bioorganic Chemistry Polish Academy of Sciences in Poznan
contact email	lukasmar@ibch.poznan.pl
lab head
Lukasz Marczak
contact affiliation	Institute of Bioorganic Chemistry Polish Academy of Sciences
contact email	lukasmar@ibch.poznan.pl
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD024945
     1. Label: PRIDE project
     2. Name: LC-MS/MS of SCA3 knock-in mouse cortex, cerebellum, and axons