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Modified Yeast-Two-Hybrid System to Identify Proteins Interacting with the Growth Factor Progranulin
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Changes in matrix metalloprotease activity and progranulin levels may contribute to the pathophysiological function

Mareike Caesar1, Sandra Felk, Susanne Zach

  • 1Boehringer Ingelheim Pharma GmbH & Co KG, CNS Diseases Research, Biberach an der Riss, Germany.

Glia
|March 22, 2014
PubMed

Insights

Leucine-rich repeat kinase 2 (LRRK2) mutations in Parkinson's disease are linked to reduced progranulin (PGRN) and increased inflammation in immune cells. This suggests immune cell inflammation may drive early Parkinson's disease stages in LRRK2 carriers.

Area of Science:

  • Neuroscience
  • Immunology
  • Genetics

Background:

  • Leucine-rich repeat kinase 2 (LRRK2) mutations are a common genetic cause of Parkinson's disease (PD).
  • Progranulin (PGRN), an anti-inflammatory protein, is implicated in neurodegenerative diseases.
  • The role of LRRK2 in immune cell function and its relation to PGRN in PD pathogenesis is under investigation.

Purpose of the Study:

  • To investigate the impact of LRRK2 mutations on PGRN levels and immune cell activity.
  • To explore the association between LRRK2, PGRN, and inflammation in the context of Parkinson's disease.

Main Methods:

  • Analysis of PGRN and pro-inflammatory factor levels in conditioned media from LRRK2 mutant mouse and human cell cultures (fibroblasts, leukocytes, microglia).
  • Assessment of mitochondrial function in human fibroblasts.
  • Measurement of matrix metalloproteinase (MMP) levels and activity in microglia and brain synaptoneurosomes.
  • Quantification of PGRN levels in cerebrospinal fluid (CSF) from LRRK2 mutant mice and PD patients.

Main Results:

  • LRRK2 mutations reduced PGRN levels and increased pro-inflammatory factors (e.g., IL-1β) in various immune cells.
  • Decreased PGRN was observed in human fibroblasts from presymptomatic LRRK2 mutation carriers.
  • Altered MMP activity and increased synaptic MMP activity were noted in LRRK2 mutant brains.
  • PGRN levels in CSF differed between presymptomatic and symptomatic LRRK2 mutant mice and were elevated in LRRK2-mutant PD patients.

Conclusions:

  • LRRK2 mutations are associated with reduced PGRN and heightened pro-inflammatory activity in peripheral and brain-resident immune cells.
  • These immune-related changes may contribute to the early pathogenesis of LRRK2-associated Parkinson's disease.
  • PGRN levels in CSF could serve as a potential biomarker in LRRK2-mutant PD.
Keywords:
LRRK2Parkinson's diseaseinflammationmetalloproteasesmotor impairmentprogranulinα-synuclein

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