Increasing general autophagy as a treatment for neurodegenerative diseases like Parkinson's disease
Get the full length version of this episode as a podcast.
This episode will make a great companion for a long drive.
The BDNF Protocol Guide
An essential checklist for cognitive longevity — filled with specific exercise, heat stress, and omega-3 protocols for boosting BDNF. Enter your email, and we'll deliver it straight to your inbox.
Neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease are characterized by protein aggregation and mitochondrial dysfunction, due in part to mitophagy failure. An emerging strategy in the prevention and (possibly) treatment of neurodegenerative diseases is starving cells as a means to induce general autophagy to help rid the cell of protein aggregates. In this clip, Dr. Guido Kroemer describes how mitophagy contributes to the pathophysiology of neurodegenerative disease and how autophagy might mitigate these processes.
- Rhonda: Very interesting. And in the case of mitophagy here, it's also it plays an important role in the prevention of neurodegenerative diseases. Correct?
- Dr. Kroemer: Yes. So, most known neurodegenerative diseases are either caused by the aggregation of poorly built proteins that somehow create protein aggregates that are toxic for the cell. Or they can also be caused by subtle deficiencies in the autophagic and lysosomal machineries that lead to the accumulation of unfolded proteins at the end. And so, either the excessive production of unfolded proteins or their reduced removal causes a slow accumulation of these toxic protein aggregates. Remember that neurodegenerative diseases are slow processes in most cases that manifest with old age. And so, one strategy to treat neurodegeneration, at least theoretically, is to increase autophagic turnover. And so, one technique is actually then to stimulate general autophagy by increasing the demand, by starvation, or by biochemical tricks that substitute for starvation, and to reduce the protein aggregates that are the cause of the disease.
- Rhonda: So these protein aggregates like amyloid-beta plaques in Alzheimer's disease or alpha-synuclein in Parkinson's disease. So, basically, the clearing out of those protein aggregates obviously would play an important role not only in prevention but presumably also, to some degree, in help with the treatment. Of course, that's you know, speculation, but... And then the mitochondria, the one I was thinking about with mitophagy, was the role, at least some of the proteins that are involved in that, like, the PINK/Parkin, and how they seem to be important for Parkinson's disease. Is that accurate?
- Dr. Kroemer: Yeah. So the PINK/Parkin pathway is one pathway among others, that allows for marking mitochondria that are damaged for destruction. And so, inhibition of this pathway leads to the accumulation of malfunctioning mitochondria with major consequences for the cell that harbors cells' mitochondria because all of a sudden bioenergetic metabolism becomes inefficient, reactive oxygen species are produced, and as you know, mitochondria are latent bombs in the sense that they enclose potentially dangerous proteins that once released will activate the apoptotic machinery and cause cellular suicide.
- Rhonda: Yeah.
A protein present in the human brain, found primarily at the synapses – the junctions between neighboring neurons where the exchange of electrical signals and neuronal communication occurs. Aggregation, or clumping, of alpha-synuclein proteins is a hallmark of Parkinson's disease, a neurodegenerative disorder of the central nervous system. Hsp70, a heat shock protein, has been shown to reduce formation of alpha-synuclein oligomers and reduce associated toxicity.[1]
- ^ Hashimoto, Tadafumi; J. McLean, Pamela; Danzer, Karin M.; Ruf, Wolfgang P.; Putcha, Preeti; Joyner, Daniel, et al. (2010). Heat‐shock Protein 70 Modulates Toxic Extracellular Α‐Synuclein Oligomers And Rescues Trans‐Synaptic Toxicity The FASEB Journal 25, 1.
A neurodegenerative disorder characterized by progressive memory loss, spatial disorientation, cognitive dysfunction, and behavioral changes. The pathological hallmarks of Alzheimer's disease include amyloid-beta plaques, tau tangles, and reduced brain glucose uptake. Most cases of Alzheimer's disease do not run in families and are described as "sporadic." The primary risk factor for sporadic Alzheimer's disease is aging, with prevalence roughly doubling every five years after age 65. Roughly one-third of people aged 85 and older have Alzheimer's. The major genetic risk factor for Alzheimer's is a variant in the apolipoprotein E (APOE) gene called APOE4.
A toxic 42 amino acid peptide that aggregates and forms plaques in the brain with age. Amyloid-beta is associated with Alzheimer's disease, a progressive neurodegenerative disease that can occur in middle or old age and is the most common cause of dementia. Heat shock proteins have been shown to inhibit the early aggregation of amyloid beta 42 and reduce amyloid beta plaque toxicity [1].
An intracellular degradation system involved in the disassembly and recycling of unnecessary or dysfunctional cellular components. Autophagy participates in cell death, a process known as autophagic dell death. Prolonged fasting is a robust initiator of autophagy and may help protect against cancer and even aging by reducing the burden of abnormal cells.
The relationship between autophagy and cancer is complex, however. Autophagy may prevent the survival of pre-malignant cells, but can also be hijacked as a malignant adaptation by cancer, providing a useful means to scavenge resources needed for further growth.
The thousands of biochemical processes that run all of the various cellular processes that produce energy. Since energy generation is so fundamental to all other processes, in some cases the word metabolism may refer more broadly to the sum of all chemical reactions in the cell.
Tiny organelles inside cells that produce energy in the presence of oxygen. Mitochondria are referred to as the "powerhouses of the cell" because of their role in the production of ATP (adenosine triphosphate). Mitochondria are continuously undergoing a process of self-renewal known as mitophagy in order to repair damage that occurs during their energy-generating activities.
The selective degradation of mitochondria by autophagy. It often occurs in defective mitochondria following damage or stress. Mitophagy is key in keeping the cell healthy. It promotes turnover of mitochondria and prevents accumulation of dysfunctional mitochondria, which can lead to cellular degeneration.
A broad range of disorders caused by the progressive death of neurons in the central and peripheral nervous systems. Common neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington’s disease, and multiple sclerosis. Although treatments are available for some neurodegenerative diseases, there are currently no cures.
A neurodegenerative disorder that affects the central nervous system. Parkinson’s disease is caused by destruction of nerve cells in the part of the brain called the substantia nigra. It typically manifests later in life and is characterized by tremors and a shuffling gait.
A biological pathway involved in mitochondrial function and surveillance. Severely damaged mitochondria lack sufficient membrane potential to import PINK1, which then accumulates on the outer membrane. PINK1 then recruits parkin to target the damaged mitochondria for degradation through autophagy. Due to the presence of PINK1 throughout the cytoplasm, PINK1 likely functions as a "scout" to probe for damaged mitochondria. Point or truncation mutations in PINK1 that reduce the kinase activity of the protein produce Parkinson’s disease with a broad phenotypic spectrum, from early-onset with atypical features to typical late-onset Parkinson’s disease.[1]
- ^ Blomgren, Klas; Kroemer, Guido (2007). Mitochondrial Cell Death Control In Familial Parkinson Disease PLOS Biology 5, 7.
Overtime proteins unintentionally accumulate damage from reactive oxygen and nitrogen species. These compromised proteins aggregate together and can promote aging as well as progressive diseases such as Alzheimer's and Parkinson's disease.
Member only extras:
Learn more about the advantages of a premium membership by clicking below.
Hear new content from Rhonda on The Aliquot, our member's only podcast
Listen in on our regularly curated interview segments called "Aliquots" released every week on our premium podcast The Aliquot. Aliquots come in two flavors: features and mashups.
- Hours of deep dive on topics like fasting, sauna, child development surfaced from our enormous collection of members-only Q&A episodes.
- Important conversational highlights from our interviews with extra commentary and value. Short but salient.
