Autophagy is an intracellular quality control and stress-response mechanism, which ensures degradation of intracellular material such as misfolded or aggregated proteins and damaged organelles, thereby cleaning the cell from potential cytotoxic waste and recycling important building blocks for organelle biogenesis and energy conservation. The dysregulation of autophagy is associated with several pathologies, including neurodegeneration. Over the past decades, the regulation and dysfunction of autophagy has mostly been investigated in non-neuronal systems. More recently, with the emerging implications of autophagy dysregulation for neurodegenerative disorders and the advancement of investigative techniques, however, the focus has also shifted onto the neuronal system.

In August 2024, Nature Reviews Molecular Cell Biology published a review by Ralph Nixon and David Rubinsztein, highlighting the critical role of autophagy-lysosome dysfunction in neurodegenerative diseases. This review emphasizes the importance of a functional autophagic-endolysosomal trafficking system in neuronal cells based on two very distinct cell/neuronal characteristics:

1. Fully developed neurons are in a post-mitotic state and are thus not able to reduce cytoplasmic waste (e.g. damaged proteins or organelles) by cell division. This makes the cells especially sensitive to age-related cellular damage.
2. Axonal and dendritic connections can range over long distances, which results in a comparatively much larger cytoplasmic volume of these cell types. Lysosomes are found mainly in the cell soma, therefore retrograde transport is essential.

The authors focus on several aspects of autophagosome-lysosome related disease progression. The key findings are summarized in this article.

Autophagosomal/autopophagic-lysosomal impairments in organismic ageing.

“In the absence of a highly penetrant disease-causing gene mutation, declining function of autophagy and particularly lysosomes, known to be driven by ageing-related factors such as oxidative damage to substrates and ELA network components, represents a basis for the emergence of manifest disease”.

The authors state that, often, sporadic forms of neurodegenerative diseases, are caused by cumulative effects of cell aging. Important drivers of cellular aging are decreased autophagosome biogenesis, deceleration of lysosomal trafficking processes, and impaired lysosomal acidification. Divided in chapters, the authors focus on mutations in various steps within the ELA axis and their association with neurodegenerative diseases in past and recent research.

Upstream autophagy defects that associate with neurodegeneration

Mutations in genes involved in the upstream stages of the autophagy-lysosome pathway play a significant role in neurodegenerative diseases. These mutations, such as in ATG5, WIPI2, and ATG7, disrupt the formation of autophagosomes, leading to neurodevelopmental disorders and potentially contributing to neurodegeneration later in life. Additionally, mutations in the ESCRT complex, which is crucial for autophagosome closure and scission, can impair autophagic flux, leading to the accumulation of toxic cellular components. Additional important factors are specific autophagy receptors, such as p62 and optineurin, selectively targeting damaged proteins and organelles for degradation. Failures in upstream autophagy pathways contribute to the accumulation of aggregate-prone proteins and dysfunctional organelles, driving the progression of neurodegenerative diseases such as Amyotrophic Lateral Sclerosis, Frontotemporal dementia, and Parkinson’s disease.

Downstream autophagy defects that associate with neurodegeneration

Lysosomal dysfunction is increasingly recognized as a key driver in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and frontotemporal lobar degeneration. Initially considered a secondary response to the accumulation of toxic proteins, lysosomal failure is now understood to be central to disease progression. Mutations in lysosomal genes disrupt the degradation of pathogenic proteins, leading to their accumulation and modification into more toxic forms. This accumulation exacerbates neuronal damage and accelerates neurodegeneration.

Central to lysosomal function is the maintenance of an acidic environment, essential for activating hydrolytic enzymes that break down cellular waste. Mutations affecting the vacuolar H+-ATPase (v-ATPase) complex, crucial for regulating lysosomal pH, have been implicated in various neurodegenerative diseases. For example, mutations in the PSEN1 gene, associated with familial AD, impair v-ATPase activity, leading to lysosomal deacidification and the accumulation of amyloid beta, driving neuronal death. Another example is mutations in TMEM175, a lysosomal proton channel, and LAMPs, which are speculated to regulate lysosomal proton leak, further disrupt lysosomal pH balance, exacerbating the buildup of toxic proteins

These pH imbalances, coupled with disruptions in calcium signaling, contribute to a state of autophagic stress, where the normal balance between autophagosome formation and clearance is lost. This stress is particularly evident in AD, where the failure to clear amyloid beta and other waste products leads to a cascade of neurotoxic events, culminating in neuronal death and plaque formation.

Future directions for clinical translation

The final chapter discusses future directions for translating autophagy-lysosome pathway research into clinical therapies for neurodegenerative diseases. It emphasizes the need to understand specific defects in the autophagy process for each disease, as therapeutic strategies may differ depending on whether early or late stages of the pathway are affected. For example, boosting autophagosome formation could be beneficial in diseases such as Parkinson’s caused by early-stage defects, but could exacerbate toxicity in conditions such as Alzheimer’s where later-stage lysosomal dysfunction is prominent. The authors also highlight ongoing efforts to identify drugs that enhance autophagy and lysosomal function, while noting the challenges in ensuring safety, specificity, and proper timing of these interventions. Despite these challenges, the potential of targeting lysosomal dysfunction in animal models shows promise, and there is optimism that autophagy modulation could become a viable therapeutic approach for neurodegenerative diseases.

This article refers to:

Nixon RA, Rubinsztein DC (2024) Mechanisms of autophagy-lysosome dysfunction in neurodegenerative diseases. Nat Rev Mol Cell Biol 25:926–946. DOI: 10.1038/s41580-024-00757-5