Autophagy, Parkinson's Disease, and Dopaminergic Neurons

Autophagic dysfunction is strongly linked with alpha-synuclein accumulation and disease progression in PD. Wu et al. (Wu, 2011) identified significant alterations in the expression of key autophagy genes, including LAMP2, and MAP1LC3, in patients with sporadic PD. The differential expression of these autophagy genes suggests these genes have the potential to serve as clinical biomarkers of PD through gene expression profiling methods like PCR (qPCR) and high-throughput sequencing technologies like RNA-Seq. 

In mouse models of PD, early-stage induction of autophagy with rapamycin was shown to have a neuroprotective effect (Pupyshev, 2019). Similarly, in a 6-hydroxydopamine (6-OHDA) model, inhibition of autophagy with 3-methyladenine was shown to prevent cell death in dopaminergic neurons (Li, 2011). These contrasting findings highlight the complex and stage-dependant role of autophagy in PD.

The degradation of defective mitochondria through a selective form of autophagy, known as mitophagy, is an essential mechanism for cell homeostasis. A growing body of research points to mitochondria dysfunction as a major player in the pathogenies of PD (Moon, 2015). These mitochondria may be a target of alpha-synuclein-induced injury, as studies in Drosophila models suggest that mutant forms of alpha-synuclein can suppress mitophagy. However, the precise molecular mechanisms underlying this suppression are not fully understood (Krzystek, 2021; Kinnart, 2024)

Lysosomal lipid metabolism is the process through which the lysosome degrades and recycles lipids within a cell in order to maintain homeostasis. In the CNS, lipids are integral for neurogenesis, formation of synapsis between neurons, and axonal insulation. In PD, mutations in genes regulating lysosome metabolism—GBA, GALC, SMPD1 and ASAH1—are known to increase the risk of developing the disease. However, the underlying mechanisms by which abnormal lipid metabolism contributes to PD are unknown.

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Alpha-synuclein: a presynaptic neuronal protein that is genetically and neuropathologically associated with Parkinson's disease (PD). 

Autophagy: derived from the Greek word meaning “self-eating”, autophagy was coined by Belgian biochemist Christian de Duve to describe a lysosomal degradative process within cells for the removal and recycling of cellular debris.

Biomarker: a measurable indicator of a biological state or condition. Biomarkers are often used in medicine and research to detect or monitor the presence, progress, or severity of a disease, as well as to assess the effectiveness of a treatment.  

Chaperone-mediated autophagy: a type of selective autophagy that uses proteins as chaperones to direct other abnormal proteins to the lysosome for degradation.

Dopaminergic neurons: neurons that produce and release dopamine, a neurotransmitter involved in motor function, reward processing, behavior, and mood. These neurons are primarily produced in a region of the brain called substantia nigra.

Electron Microscopy (EM): an imaging technique that utilizes a beam of electrons to visualize structures with nanometer-scale resolution.

Exosomes: extracellular membrane-bound vesicles excreted by eukaryotic cells for the purpose of transporting various biomolecules between cells.

Lewy bodies: large deposits of alpha-synuclein that accumulate within neurons. These clumps are hallmark of Parkinson’s disease.

Limbic system: a complex network of structures in the brain involved in emotions, behaviours, motivation, and memory.

Lysosome: a membrane-bound degradative organelle in eukaryotic cells, responsible for digesting lipids, proteins, and other macromolecules.

Microglia: one of the neuroglial cell types present in the brain and spinal cord. Constituting approximately 10-15% of the total cellular population in the brain, microglial cells function as the primary immune cells of the central nervous system. These cells are essential for maintaining homeostasis, clearing cellular debris, and providing critical support functions within the brain. 

Neurodegeneration: a complex, multifactorial process resulting in the loss of neurons.  

Parkinson's Disease (PD): a neurodegenerative disease that is characterized by: (a) movement-related (motor) symptoms, including resting tremor, bradykinesia, rigidity, and postural instability, related to the loss of dopaminergic neurons in the substantia nigra; and (b) non-motor symptoms including anxiety, depression, apathy, hallucinations, constipation, orthostatic hypotension, sleep disorders, hyposmia/anosmia, and cognitive impairment.  

Misfolded proteins: proteins are composed of linear chains of amino acids that must fold into a functional three-dimensional structure. When these chains fail to fold properly, the resulting proteins can adopt abnormal shapes. These proteins are typically insoluble, and disrupt normal cellular processes. The accumulation of misfolded proteins is closely linked with several neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Amyotrophic lateral sclerosis (ALS).

Protein aggregates: clusters of misfolded proteins that clump together inside or around cells like tangled balls of yarn.

Substantia nigra: a dopaminergic nucleus in the midbrain which plays a critical role in modulating motor and reward functions as part of the basal ganglia circuitry.

Transactive response DNA binding protein of 43 kDa (TDP-43): a highly conserved nuclear RNA/DNA-binding protein encoded by the TARDBP gene involved in the regulation of RNA processing.