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Printable Handouts
Navigable Slide Index
- Introduction
- Parkinson’s disease: symptoms and pathology
- Parkinson’s disease: pathology progression
- Parkinson’s disease: pathology
- 2002: a new locus
- 2004: Basque families
- 2004: a British family
- 2004-2005: familial variants
- 2005: a common variant
- LRRK2 domains and mutations
- ROC: COR mutations lower GTPase
- LRRK2 p.G2019S increases kinase
- LRRK2 regulates a subset of Rab GTPases
- Multiple mutations enhance kinase
- Is this kinase activity important for pathogenesis?
- Kinase inhibitors in vivo
- Summary of data
- Genome-Wide Association Study (GWAS)
- Two GWAS signals
- Variable penetrance
- Pleomorphic risk locus
- LRRK2 affects endolysosome in vivo: experiments in knock-out mouse
- LRRK2 affects endolysosome in vivo: experiments with lysosomal inhibitor
- LRRK2 rarely labels lysosomes
- LRRK2 at damaged lysosomes
- Lysosomal tubulation/sorting
- Lysosomal tubulation/sorting driven by LRRK2 (LYTL)
- Lysosomal repair pathways
- Membrane targeting activates LRRK2
- Peripheral localization limits LRRK2
- LRRK2 activation pathways
- LRRK2 in immune cells
- A parallel mechanism in neurons
- Single-cell brain expression by genotype
- LRRK2 in human frontal cortex
- A microglial eQTL
- Microglial open chromatin
- Single-cell validation of iPSC-derived cells
- LRRK2 activity in IPSC
- Single-cell validation of iPSC-derived cells
- Single-cell screen for functional variants (1)
- GWAS results
- Single-cell screen for functional variants (2)
- Inflammation and lysosomal gene expression
- Age increased LRRK2 in microglia
- Summary
Topics Covered
- Role of LRRK2 in Parkinson’s disease
- Coding variants and non-coding variants of Parkinson’s disease
- LRRK2 domains and mutations
- LRRK2 regulates a subset of Rab GTPases
- Microglia as mediators of disease risk within the brain
- Microglia are important in neuroinflammation and change with aging
Links
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External Links
Talk Citation
Cookson, M. (2023, December 31). Leucine-rich repeat kinase 2 (LRRK2) [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved October 12, 2024, from https://doi.org/10.69645/MJAI4675.Export Citation (RIS)
Publication History
Financial Disclosures
- There are no financial matters to disclose.
A selection of talks on Neurology
Transcript
Please wait while the transcript is being prepared...
0:00
Today, I'm going to
talk to you about
Leucine-rich repeat
kinase 2 or LRRK2.
My name is Mark Cookson.
I'm the Chief of the
Laboratory of Neurogenetics at
the National Institute on Aging.
0:13
First, let me tell you a little
bit about Parkinson's disease,
what it is, and how it
expresses itself in humans.
Parkinson's disease
is a motor disorder.
It's characterized by tremors,
bradykinesia, or
slowness of movement,
rigidity, posture, and gait.
However, Parkinson's disease is
also a multisystem disorder,
so you can have
prodromal symptoms
that occur before
the onset of motor
Parkinson's disease
including things
like REM sleep
behavioral disorder.
Often, later on in
the disease course,
Parkinson's disease
can develop into
a dementing illness
characterized
by cortical dysfunction.
The pathology of Parkinson's
disease is really two parts.
First of all, the cell loss,
and very prominently
dopamine neurons in
the substantial
nigra pars compacta
that project to the
striatum are lost.
But the pathology is also
protein accumulation
pathology and
we have Lewy bodies that
are present across
different brain regions.
1:06
Illustrated here by the
work of Heiko Braak et al.,
you can see that the Lewy
body pathology starts in
very deep brain stem areas
and then progresses up
through the midbrain and then
eventually, into the
cerebral cortex.
1:21
Parkinson's disease pathology is
also a multicellular process.
For example, I said
earlier that neurons and
substantia nigra the
dopamine neurons that
project the striatum are
lost in the disease.
But this is also associated with
the activation of cells
around those dying neurons,
including astrocytes
and microglia.
If we think of
Parkinson's in this way,
it's a multi-system,
multi-pathology, and
multicellular disorder.