Accumulation of the protein alpha-synuclein in the brain — a hallmark of neurodegenerative diseases like Parkinson’s — does not factor in the early disease course of Sanfilippo syndrome type A, a mouse study suggests.
The study, “Early disease course is unaltered in MPS IIIA mice lacking α-synuclein,” was published in the journal Neuropathology and Applied Neurobiology.
Alpha-synuclein, a protein found in neurons, has key functions within nerve cells, including the release of neurotransmitters: chemical substances produced in response to nerve signals that allow these cells to communicate.
The buildup of abnormal (misfolded) alpha-synuclein is a hallmark of diseases like Parkinson’s and Gaucher.
Previous research has shown that alpha-synuclein accumulates in brain lesions of people with Sanfilippo syndrome, suggesting that it could affect the release of certain neurotransmitters. The same was observed in mouse models of the disease.
Researchers wondered if a buildup of alpha-synuclein played a role in the emergence of symptoms (those occurring in mice in a disease model at 3–5 months of age) early in the disease’s course, including impaired cognition, anxiety, and motor deficits.
They engineered different mouse models of Sanfilippo type A that carried either two or one copy of the alpha-synuclein gene (SNCA), or no copy. Mice with two or one SNCA copies would be deficient for the protein; those with no copies completely lack the protein.
They then performed a series of behavioral tests, at earlier (12 weeks) and later (22 weeks) stages of the disease, and compared results between the three different mouse models with that of normal (wild-type) mice.
Researchers used the open-field and Morris water maze tests to evaluate the animals’ performance. The open-field test measures an animal’s ability to explore, while the water maze test measures location-associated learning and memory. They put the mice through the elevated plus maze test, which measures anxiety-like behaviors (mice have a natural aversion to open and elevated areas), and the animals’ walking capacity (gait test).
All Sanfilippo mice, regardless of alpha-synuclein level, were significantly impaired in behavioral test performance compared to wild-type littermates. Walking distance and speed were also poorer in all Sanfilippo mice.
Molecular analysis showed that independently of alpha-synuclein, heparan sulphate — a complex sugar molecule that accumulates inside cell structures called lysosomes in Sanfilippo patients — and other sugar-fat molecules called gangliosides accumulated within the brains of all Sanfilippo mice.
Further brain tissue analysis revealed the presence of lesions with alpha-synuclein buildup in Sanfilippo mice with one and two copies of the alpha-synuclein gene, and none in animals that lacked the SNCA gene.
Although absent in all mice at three weeks of age, a large number of ubiquitin inclusions (clumps) were present in the brains of all Sanfilippo mice by 12 weeks of age, particularly in the brainstem. This brain region is involved in such basic physiological functions as heart rate, breathing, sleeping, and eating.
Ubiquitin is a protein that helps to regulate the processes of other proteins in the body, including degrading those that are no longer of use or are not working properly.
The number of ubiquitin inclusions significantly increased by 22 weeks of age, except in the motor cortex and striatum: two brain regions involved in cognition, motor planning, and the execution of voluntary movements.
The presence of lesions resulting from the accumulation of these two proteins seems to indicate an impairment in natural protein degrading systems.
These results suggest that alpha-synuclein “in and of itself … does not initiate the cognitive and motor symptoms that occur in the first five months of life in [Sanfilippo type A] mice,” the researchers concluded.
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