Autophagy, derived from the Greek words for "self-eating," is one of the most critical processes in our cells.
It acts as a housekeeping system, breaking down and recycling "waste" materials, such as damaged cell parts, worn-out proteins, and even entire organelles like mitochondria. Think of it as the body’s natural way of tidying up its cells to maintain their health and efficiency.
Our cells are bustling with proteins - tiny molecular machines that perform countless functions, from building cell structures to transmitting signals and facilitating chemical reactions.
Over time, proteins can become damaged or misfolded, much like how machinery can wear out. When this happens, they need to be cleared out to prevent them from accumulating and disrupting cellular function. This happens via autophagy.
Besides proteins, larger cell components, like mitochondria, also need to be broken down and recycled, especially when they are old or damaged.
There exist 3 forms of autophagy:
- Macroautophagy: this is the major pathway. Cells use it to mainly break down large cell components, like mitochondria. This happens by enveloping components in a vesicle and then fusing this vesicle with a lysosome, which is a tiny vesicle that is very acidic and contains enzymes to break down cell components.
- Microautophagy: more used for smaller cell components, like proteins and protein aggregates. The lysosome itself engulfs these substances, and then digests them.
- Chaperone-Mediated Autophagy (CMA): this is a very selective pathway, in which specific proteins are “tagged” or “labeled” by a protein (called Hsc70) so they can be shuttled into the lysosome for breakdown.
Besides autophagy, there is also the ubiquitin-proteasome system (UPS). Here, specific proteins (including misfolded proteins) are tagged with a small molecule called ubiquitin, which acts as a signal for degradation. The ubiquitinated proteins are then directed to the proteasome, a barrel-shaped protein complex, for degradation.
The ubiquitin-proteasome system is highly specific, and is mainly involved in the maintenance and recycling of short-lived, damaged, or misfolded proteins.
Parkinson’s Disease and Protein Accumulation
In Parkinson’s disease, as well as during normal aging, specific proteins start to pile up in the brain. One of the reasons for this can be a decline in autophagy.
One of the most infamous culprits is alpha-synuclein, a small protein composed of 140 amino acids.
Under normal circumstances, alpha-synuclein plays essential roles in cellular processes, such as the transport of tiny vesicles (bubble-like structures that carry molecules inside cells) and possibly DNA repair.
However, in Parkinson’s disease, alpha-synuclein can misfold and clump together, forming structures known as Lewy bodies.
These protein aggregates disrupt the normal functioning of neurons (brain cells) and eventually lead to their death. The loss of neurons in specific areas of the brain, like the substantia nigra, results in the hallmark symptoms of Parkinson’s disease, such as tremors, stiffness, and difficulty with movement.
Why Does Autophagy Decline?
Researchers are still uncovering the reasons behind impaired autophagy in Parkinson’s disease.
For instance, mutations or changes in alpha-synuclein change its structure, so this protein aggregates more easily.
Mutations in genes like LRRK2 and GBA, which are linked to Parkinson’s disease, can directly affect the autophagy process (learn more about the genetics of Parkinson’s disease here).
Therapies for Autophagy
Scientists are exploring therapies aimed at boosting autophagy to enhance the brain’s ability to clear out harmful proteins.
Some of these approaches include small molecules that stimulate autophagy, gene therapies, and lifestyle interventions like fasting and exercise, which have been shown to increase autophagy activity.
You can learn more about the latest therapies for Parkinson’s disease here.
