The secret power of lysosomes to cure Parkinson’s and Alzheimer’s

Author:

Pasquale Pellegrini holds an M.Sc. in Biotechnology from Università degli Studi di Bari (Italy). He moved to Barcelona to pursue his Ph.D. at the Bellvitge Biomedical Research Institute (IDIBELL), in Barcelona, where he uncovered key mechanisms of mammary stem cell differentiation and tumor initiation. He is currently a Postdoctoral scholar at the Gladstone Institutes in San Francisco where he is investigating the lysosome network in several neurodegenerative diseases.

What are lysosomes doing inside your cells?

When I was in High School my teacher used to say that lysosomes are only the trash bin of the cell. 20 years later we have discovered a dozen new functions that make this small organelle a core component of the cell.

You may already know that the lysosome pH is extremely low (around 4.5). Such an acidic environment activates lysosomal enzymes that destroy everything including proteins and entire organelles. However, you probably don’t know that lysosomes also regenerate the plasma membrane, regulate the intracellular Calcium and are the control center of energy metabolism ¹.

The key function that many laboratories and biopharma companies are trying to elucidate now is how lysosomes regulate autophagy: the process by which every cell degrades its abnormal proteins and entire organelles (see picture below).

What do lysosomes have to do with Alzheimer’s and Parkinson’s?

Let’s take a step back and think about neuronal life. A neuron does not go through mitosis: if it dies, it’s over,you don’t get a new one. You need your neurons to stay alive and healthy as long as possible, possibly for your entire life. In order to survive for such a long time, neurons use a very efficient cleaning system: the autophagy.

Abnormalities in this process have now been described in several neurodegenerative disorders including Parkinson’s and Alzheimer’s. Dysfunctional autophagy can be due to genetic causes, aging or both.

In familiar cases of Alzheimer’s and Parkinson’s, known to have a strong genetic basis, the genes frequently mutated in these diseases impair lysosome function and autophagy.

An example is the Alzheimer’s-associated gene Presenilin-1, this protein is mostly known to be the main responsible for the formation of neurotoxic Aβ peptide, the main component of the protein aggregates found in brains of Alzheimer patients. A few years ago Dr. Ralph Nixon from the NYU School of Medicine, discovered that this protein, when mutated, impairs lysosome acidification resulting in a lower ability to clear proteins ².

Similarly, other genes such as Parkin-1 for Parkinson disease and SOD1 for Amyotrophic Lateral Sclerosis when mutated can impair autophagic degradation (Parkin-1) and lysosome movement (SOD1) leading to an abnormal autophagy and accumulation of undigested protein aggregates.

Thanks to genetic studies, the mechanisms underlying protein aggregation is being elucidated. Unfortunately, only 5-15% of the patients present a genetic mutation. The majority of cases manifest as a late-onset sporadic form with no evidence of gene mutations. A full understanding of the causes of the sporadic form is still not yet in reach.

The aged lysosome

Both Alzheimer’s and Parkinson’s disease are age-related progressive neurodegenerative disorders.

Aging has an impact on autophagy: as we get old, this process becomes less efficient ³. Probably the same thing is occurring in the lysosome organelle. In older people, lysosomes accumulate junk that cannot be degraded called lipofuscin. If the autophagy doesn’t work well and lysosomes are not so good to degrade the proteins they receive from the autophagy process we can imagine a scenario where undegraded proteins accumulate and form toxic aggregates that kill neurons.

The promise of fresh new lysosomes

How the cell controls lysosomal function has remained unanswered for a long time. The discovery of a gene network regulating lysosomal biogenesis called CLEAR has been a huge advance in lysosome biology ⁴.

For the first time, scientists were able to modulate this network to specifically induce the formation of new lysosomes. Apparently inducing the formation of new lysosome was enough to clear protein aggregates and improve cognitive symptoms in mouse models of Alzheimer’s and Parkinson’s disease ⁵.

However, when we induce the formation of new lysosomes these can fuse with the cell membrane and discharge their content outside of the cell. Such a mechanism can be dangerous in neurodegeneration: what if the secreted toxic proteins are released outside and introduced in another healthy cell? Further studies will be necessary to develop safe lysosome inducers.

An alternative approach to inducing lysosome function comes from the acidic nanoparticles, these particles can enter inside the cell, reach lysosomes and lower the pH. The low pH makes degradation easier because it activates the lysosomal enzymes. The usage of these particles restored the normal pH and reduced the abnormalities in the autophagy pathway in a mouse model of Alzheimer’s disease ⁶.

A lysosome drug in clinical trials

A promising drug for neurodegenerative diseases is a chemotherapy used for leukemias called Nilotinib. Pre-clinical studies in mouse models of Parkinson’s disease demonstrated that this drug induces the degradation of alpha-synuclein, the main component of protein aggregates, by the lysosomes. Dr. Charbel Moussa from the Georgetown University Medical Center in Washington DC led a trial in 12 volunteers with Parkinson’s disease. The trial was initially designed to test only the safety of the drug via oral administration. Even though the stage of the disease was advanced, all patients started to improve their motility and ability to speak in a few weeks after taking the drug.

“We had people as stiff as a board at the start of the study who were walking around, sitting down and bending their legs by the end,” says Moussa, “You could see the elation on their faces when they saw the improvement. There wasn’t a dry eye in the room.”

The drug was detectable in the cerebrospinal fluid of the participants, demonstrating that it could actually reach the brain of the patients and there was a correlation between the dose of nilotinib and the improvement of the symptoms⁷. Further clinical trials are planned to confirm the drug’s safety and efficacy.

Final remarks

An estimated seven to 10 million people worldwide are living with Parkinson’s disease. 46 million people worldwide live with dementia, including Alzheimer’s.

There is a growing literature indicating the importance of lysosome function in neurons and neurodegeneration. Developing drugs that induce lysosome function will target the root cause of neurodegeneration and possibly cure these terrible diseases.