Alpha-Synuclein Not Responsible for Early Symptoms of Sanfilippo Type A, Study Shows

Alpha-synuclein protein is not responsible for the onset of cognitive and motor symptoms associated with 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 Neuropathology and Applied Neurobiology.

Sanfilippo syndrome type A, also called mucopolysaccharidosis type IIIA (MPS IIIA), is characterized by impaired activity of the SGSH gene. This gene gives instructions to produce an enzyme called sulfamidase, which, when defective, results in the accumulation of large sugar molecules, called heparan sulfate, inside cells.

The disease mainly affects the central nervous system (the brain and spinal cord), leading to progressive neurodegeneration, and mental and behavioral symptoms including aggressive behaviors, hyperactivity, language difficulties, and sleep disturbances.

Many studies point to heparan sulfate accumulation as the culprit in neurodegeneration in Sanfilippo syndrome. However, it remains unclear whether this molecule is the primary cause of brain damage or a secondary effect of other mechanisms.

Researchers at the South Australian Health and Medical Research Institute (SAHMRI) had previously shown that some proteins, including alpha-synuclein, tau, and beta-amyloid, could form spheroid (round) aggregates and accumulate inside mice brain nerve cells at pre-symptomatic stages of the disease.

Supported by these findings, and given that alpha-synuclein is a well-known contributor to neurodegeneration in other human diseases, such as Parkinson’s disease, the team decided to further explore the role of alpha-synuclein in Sanfilippo syndrome type A.

Mice were genetically manipulated to have either very low levels of or no alpha-synuclein protein, in addition to having impaired sulfamidase enzyme activity.

The absence or low levels of alpha-synuclein protein did not cause any significant physical change to the animals at birth compared to Sanfilippo mice with normal levels of the protein. As they grew, all mice began to show an aggressive behavior with progressive abnormal posture and more limited movement. Impaired cognitive responsiveness and abnormal gait patterns observed in Sanfilippo mice were similar among animals, independently of the levels of alpha-synuclein.

Also, analysis of several biomarkers of neurodegeneration and accumulation of toxic proteins revealed there was a similar disease progression pattern throughout the animals’ lifespan, with no significant impact of alpha-synuclein levels.

Collectively, these results suggest that alpha-synuclein does not influence some of the hallmark biological mechanisms of Sanfilippo syndrome type A in mice.

“Our findings are important in that they highlight the fact that altered [levels] of alpha-synuclein [do] not contribute significantly to the appearance of [cognitive and motor] symptoms” emergent early in the course of Sanfilippo syndrome type A in mice,” the researchers said.