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Basic Science and Pathogenesis.

Silas A Buck1, John F Ervin1, Shih-Hsiu Jerry Wang1

  • 1Duke University Medical Center, Durham, NC, USA.

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Summary
This summary is machine-generated.

Leucine-rich repeat kinase 2 (LRRK2) activity markers correlate with tau pathology and granulovacuolar degeneration bodies (GVBs) in neurodegenerative diseases. This suggests LRRK2 phosphorylation of Rab proteins may contribute to GVB and tau accumulation.

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Area of Science:

  • Neurobiology
  • Neurodegenerative Diseases
  • Molecular Biology

Background:

  • Alzheimer's disease (AD) and primary tauopathies feature pathological tau aggregation.
  • Synucleinopathies, including Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB), also show tau pathology.
  • LRRK2 gene mutations cause autosomal dominant PD, with common alpha-synuclein and tau pathology.

Purpose of the Study:

  • Investigate the correlation between LRRK2 kinase activity markers and tau pathology in neurodegenerative diseases.
  • Determine if LRRK2 activity is linked to alpha-synuclein or tau pathology in human conditions.
  • Explore the role of LRRK2 in the formation of granulovacuolar degeneration bodies (GVBs).

Main Methods:

  • Immunohistochemical labeling of brain tissue from AD, DLB, idiopathic PD (iPD), LRRK2 PD, and controls.
  • Utilized phospho-Rab10 T73 (pRab10) and phospho-Rab12 S106 (pRab12) as LRRK2 kinase activity markers.
  • Performed immunofluorescence of pRab12 in PS19 mice overexpressing mutant human tau.

Main Results:

  • Increased pRab12 area observed in AD, DLB, iPD, and LRRK2 PD, localizing to tau aggregates and Lewy bodies.
  • pRab10 and pRab12 labeled granulovacuolar degeneration bodies (GVBs) in all disease groups.
  • Replicated pRab12 GVB labeling in PS19 mice, confirming pathological tau triggers pRab12-positive GVBs.
  • GVBs are lysosomal structures (LAMP1 positive) containing a pRab12-positive core.
  • pRab12-positive GVBs co-localized with phosphorylated tau (AT8) and mitophagy markers.

Conclusions:

  • LRRK2 kinase activity markers correlate with tau pathology and GVB accumulation in neurodegenerative diseases.
  • Pathological tau triggers pRab12-positive GVBs, which are lysosomal structures.
  • LRRK2-mediated phosphorylation of Rab proteins may contribute to tau and GVB pathology in these diseases.