Brain astrocytes show metabolic alterations in Parkinson's disease


Date:
September 8, 2020
Source:
University of Eastern Finland
Summary:
A new study using induced pluripotent stem cell (iPSC)
technology links astrocyte dysfunction to Parkinson's disease (PD)
pathology. The study highlights the role of brain astrocyte cells
in PD pathology and the potential of iPSC-derived cells in disease
modelling and drug discovery.



FULL STORY ==========================================================================
A new study using induced pluripotent stem cell (iPSC) technology
links astrocyte dysfunction to Parkinson's disease (PD) pathology. The
study carried out at the University of Eastern Finland and published in Scientific Reports highlights the role of brain astrocyte cells in PD
pathology and the potential of iPSC-derived cells in disease modelling
and drug discovery.


==========================================================================
PD affects more than 6 million people worldwide, making PD the second most common neurodegenerative disease. PD's exact cause is still unknown, but several molecular mechanisms have been identified in PD pathology. These include neuroinflammation, mitochondrial dysfunction, dysfunctional
protein degradation and alpha-synuclein (a-synuclein) pathology. The
disease's major hallmarks comprise the loss of dopaminergic neurons and
the presence of Lewy bodies and Lewy neurites. The loss of dopaminergic
neurons and the subsequent decrease in dopamine levels are considered responsible for PD's typical movement symptoms. There is no cure for
PD and currently, the treatments are targeted to alleviate the motor
symptoms with dopamine replacement therapy and surgery.

The greatest risk factor for PD is high age, but some environmental
factors, such as toxins and pesticides, have been shown to increase PD
risk. Though most PD cases are late-onset and sporadic with no evidence
for an inheritance, approximately 3-5 % are monogenic. The most common
cause for monogenic PD is mutations in the leucine-rich repeat kinase 2
(LRRK2) gene. LRRK2-associated PD is clinically closest to sporadic forms
of the disease regarding the age of onset, disease progression and motor symptoms. Additionally, mutations in the GBA (glucosylceramidase beta)
gene are the most significant risk factor for PD identified to date. The molecular mechanisms by which GBA mutations result in this increased
risk are currently the focus of substantial research efforts.

Astrocytes from patients expressed several hallmarks of Parkinson's
disease While studies focusing on dopaminergic neurons have brought
new insight into PD pathology, astrocyte contribution to PD has been investigated only sparsely.

Astrocytes are glial cells and the most abundant cell type in the
human brain.

It was long thought that the astrocytes worked solely as supporting
cells for neurons, but today the role of astrocytes is known to be far
more extensive.

Until now, only a few studies have used iPSC-derived astrocytes obtained
from PD patients. The current study used iPSC-derived astrocytes from
two PD patients carrying a mutation in the LRRK2 gene, one of them
presenting with an additional mutation in GBA to further characterize
the PD astrocyte phenotype.

The researchers found out that astrocytes from PD patients produced significantly higher levels of a-synuclein, a protein that accumulates
in PD patients' brain. One of the key pathological features caused by a-synuclein aggregation is the disruption of calcium homeostasis, and the
study showed increased calcium levels in PD astrocytes. As inflammation is considered to be an important contributor to PD pathology, the response to inflammatory stimuli was studied in astrocytes. The PD patient astrocytes
were highly responsive to inflammatory stimuli and more sensitive to inflammatory reactivation than control astrocytes. Additionally, PD
astrocytes showed altered mitochondrial function and lower mitochondrial
DNA copy number. Furthermore, PD astrocytes showed increased levels of polyamines and polyamine precursors while lysophosphatidylethanolamine
levels were decreased, both of these have been reported altered in
PD brain.

"The results provide evidence that LRRK2 and GBA mutant astrocytes are
likely to contribute to PD progression and offer new perspectives for understanding the roles of astrocytes in the pathogenesis of PD," says
Early Stage Researcher Tuuli-Maria Sonninen, the lead author of the study.


========================================================================== Story Source: Materials provided by University_of_Eastern_Finland. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Tuuli-Maria Sonninen, Riikka H. Ha"ma"la"inen, Marja Koskuvi, Minna
Oksanen, Anastasia Shakirzyanova, Sara Wojciechowski,
Katja Puttonen, Nikolay Naumenko, Gundars Goldsteins, Nihay
Laham-Karam, Marko Lehtonen, Pasi Tavi, Jari Koistinaho,
Sa'rka Lehtonen. Metabolic alterations in Parkinson's
disease astrocytes. Scientific Reports, 2020; 10 (1) DOI:
10.1038/s41598-020-71329-8 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200908113310.htm

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