Parkinson's disease involves the loss of neurons that produce dopamine and is marked by symptoms such as tremors, slow motor skills, and rigidity. A new study identified a mutation in the SGIP1 gene in individuals from the same family, responsible for synaptic function. When the experiment was replicated in fruit fly models, the gene caused problems similar to Parkinsonism, including synaptic degeneration and accumulation of non-recycled organelles.
Parkinson's disease (PD) is a neurological condition characterized primarily by motor symptoms, such as slow movements (bradykinesia), resting tremors, muscle rigidity, and postural instability, and is treated with levodopa, a medication that helps replace dopamine in the brain.
This condition results from the loss of dopaminergic neurons, or nerve cells that produce the neurotransmitter dopamine, in a region of the brain called the substantia nigra.
These motor symptoms are often accompanied by the accumulation of structures called Lewy bodies, formed by proteins that accumulate abnormally in neurons. Recent scientific discoveries suggest that the early stages of PD involve problems with the function of connections between neurons, called synapses.
Dysfunction and degeneration of these synapses can unbalance dopamine production in the brain and trigger the motor symptoms of the disease.
In addition to the common cases of PD, there is a rare and inherited form of the disease, monogenic parkinsonism, caused by mutations in genes such as SH3GL2, SYNJ1, and DNAJC6, which encode proteins essential for the proper functioning of synapses.
These mutations can lead to a more complex picture of symptoms, including intellectual disability and seizures, in addition to the traditional motor symptoms of PD. These proteins play important roles in the formation, function, and renewal of synapses, in addition to contributing to the process of autophagy, which is the recycling of damaged cellular components.
Recent studies have used advanced technologies, such as whole exome sequencing, to identify mutations in new genes, including the SGIP1 gene, found in a family with a rare case of Parkinsonism.
One specific mutation, W694G, has been associated with the loss of function of the SGIP1 protein. Experiments with fruit flies genetically modified to reproduce this mutation showed symptoms similar to those of Parkinsonism, such as loss of dopaminergic synapses and accumulation of organelles that cells would normally degrade and recycle.
Loss of dSgip1 induces widespread degeneration, including dopaminergic synapse loss. PD is associated with dopaminergic neuron dysfunction. Therefore, we assessed the integrity of these neurons in the brains of aged (25 days old) control and dSgip1−/− flies using an anti-tyrosine hydroxylase (TH) stain. Although the number of anti-TH-positive (TH+) dopaminergic neuronal cell bodies in the different groups of dopaminergic neurons was not affected (C), the synaptic area of dopaminergic neurons innervating the mushroom body (the brain structure that regulates multiple functions such as olfactory learning and memory, sleep, and locomotion) was significantly reduced in dSgip1−/− mutants compared to controls (D). Therefore, dSgip1 function is required for the maintenance of synaptic integrity of dopaminergic neurons in the fly brain.
These findings reinforce the idea that problems in the quality control of synaptic proteins and synapse balance are related to the development of PD.
Studies of this mutation have revealed that loss of SGIP1 function can cause a series of motor and behavioral symptoms that resemble human PD, such as limited movement and synaptic alterations.
This work also opens up possibilities for new methods of diagnosis and treatment, in addition to offering genetic information for family counseling.
The discoveries about the function of SGIP1 and its relationship with other synaptic proteins involved in PD represent an important advance in understanding the biological mechanisms underlying the disease and in the search for possible therapies.
READ MORE:
A candidate loss-of-function variant in SGIP1 causes synaptic dysfunction and recessive parkinsonism
Decet M et al.
Cell, Volume 5, Issue 10101749, October 15, 2024
DOI: 10.1016/j.xcrm.2024.101749
Abstract:
Synaptic dysfunction is recognized as an early step in the pathophysiology of Parkinsonism. Several genetic mutations affecting the integrity of synaptic proteins cause or increase the risk of developing disease. We have identified a candidate causative mutation in synaptic “SH3GL2 Interacting Protein 1” (SGIP1), linked to early-onset parkinsonism in a consanguineous Arab family. Additionally, affected siblings display intellectual, cognitive, and behavioral dysfunction. Metabolic network analysis of [18F]-fluorodeoxyglucose positron emission tomography scans shows patterns very similar to those of idiopathic Parkinson’s disease. We show that the identified SGIP1 mutation causes a loss of protein function, and analyses in newly created Drosophila models reveal movement defects, synaptic transmission dysfunction, and neurodegeneration, including dopaminergic synapse loss. Histology correlative light and electron microscopy reveal the absence of synaptic multivesicular bodies and the accumulation of degradative organelles. This research delineates a putative form of recessive parkinsonism, converging on defective synaptic proteostasis and opening avenues for diagnosis, genetic counseling, and treatment.
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