Summary: New finding could lead to novel therapeutic approaches in the treatment of neurodegenerative diseases.
Source: King’s College London.
Researchers at King’s College London have discovered new mechanisms of cell death, which may be involved in debilitating neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease.
This novel research, published today in Current Biology, could lead to new therapeutic approaches for treating or delaying the progression of neurodegenerative conditions that are currently incurable, if the findings are expanded. Many current treatments for neurodegenerative conditions actually aim to enhance cell clearance, which may worsen rather than improve neurodegenerative symptoms, making the need for new treatment strategies an urgent priority.
Approximately 10 million people in the UK live with a neurological condition, with dementia alone estimated to cost the economy more than £10.5 billion per year in health and social care. Neurodegenerative conditions are characterised by a progressive loss of brain function, so that patients start to lose control of their movement, balance, memory and speech – similar to what happens when people have strong alcohol intoxication.
However, it is not currently known how or why these brain cells lose function, particularly in the terminal stage of these illnesses.
Using two animal models of a degenerative neurological disorder, the researchers were able to find a similar dysfunctional process occurring in fruit flies and mice, as well as human cells, meaning that their findings are likely to be replicated in human brains. Specifically, they found that in this condition nerve cells in certain areas of the brain become stalled and are no longer able to remove toxins or old and dysfunctional brain cells, which is a naturally occurring process known as autophagy. Autophagy is essentially how the brain breaks down cellular waste to elementary pieces, which are then recycled and used to construct and renovate brain cells.
The persistent stall in autophagy means the nerve cells are unable to ‘clean’ the brain and this results in a build up of toxins. Essentially the cells become confused and begin pushing out essential inner components rather than waste, leading to a loss of function and ultimately their death.
This new insight into how nerve cells might die from self-digestion has important implications for therapeutic approaches targeting autophagy. While current treatments aim to enhance cell clearance, in this study the authors were able to disrupt specific processes that interfere with cell clearance.
Dr Olga Baron, first author from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London, said ‘Studies like ours, looking at rare genetic conditions, can be very powerful in finding new mechanisms. We are currently looking into whether we can replicate the same findings for other disorders where autophagy has been shown to malfunction, like Alzheimer’s disease and motor neurone disease.’
Dr Manolis Fanto, IoPPN, King’s College London, senior author of the study said ‘Autophagy is important for all degenerative neurological conditions and what is emerging from our study is how the blockage of autophagy kills nerve cells in a new way, not described before.’
Funding: This study was funded by the Henry Smith Charity, Ataxia UK, US National Ataxia Foundation, Medical Research Council and the NC3R.
Source: Jack Stonebridge – King’s College London
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is credited to the researchers.
Original Research: Full open access research for “Stall in canonical autophagy-lysosome pathways prompts nucleophagy-based nuclear breakdown in neurodegeneration” by Olga Baron, Adel Boudi, Catarina Dias, Michael Schilling, Anna Nölle, Gema Vizcay-Barrena, Ivan Rattray, Heinz Jungbluth, Wiep Scheper, Roland A. Fleck, Gillian P. Bates, and Manolis Fanto in Current Biology. Published online November 22 2017 doi:10.1016/j.cub.2017.10.054
Stall in canonical autophagy-lysosome pathways prompts nucleophagy-based nuclear breakdown in neurodegeneration
•Progressive stall in canonical autophagy in disease-specific areas in DRPLA
•Chronic autophagy block activates alternative degradation pathways in vivo
•Nucleophagy-associated LaminB1 accumulates in the cytoplasm and is then excreted
The terminal stages of neuronal degeneration and death in neurodegenerative diseases remain elusive. Autophagy is an essential catabolic process frequently failing in neurodegeneration. Selective autophagy routes have recently emerged, including nucleophagy, defined as degradation of nuclear components by autophagy. Here, we show that, in a mouse model for the polyglutamine disease dentatorubral-pallidoluysian atrophy (DRPLA), progressive acquirement of an ataxic phenotype is linked to severe cerebellar cellular pathology, characterized by nuclear degeneration through nucleophagy-based LaminB1 degradation and excretion. We find that canonical autophagy is stalled in DRPLA mice and in human fibroblasts from patients of DRPLA. This is evidenced by accumulation of p62 and downregulation of LC3-I/II conversion as well as reduced Tfeb expression. Chronic autophagy blockage in several conditions, including DRPLA and Vici syndrome, an early-onset autolysosomal pathology, leads to the activation of alternative clearance pathways including Golgi membrane-associated and nucleophagy-based LaminB1 degradation and excretion. The combination of these alternative pathways and canonical autophagy blockade, results in dramatic nuclear pathology with disruption of the nuclear organization, bringing about terminal cell atrophy and degeneration. Thus, our findings identify a novel progressive mechanism for the terminal phases of neuronal cell degeneration and death in human neurodegenerative diseases and provide a link between autophagy block, activation of alternative pathways for degradation, and excretion of cellular components.
“Stall in canonical autophagy-lysosome pathways prompts nucleophagy-based nuclear breakdown in neurodegeneration” by Olga Baron, Adel Boudi, Catarina Dias, Michael Schilling, Anna Nölle, Gema Vizcay-Barrena, Ivan Rattray, Heinz Jungbluth, Wiep Scheper, Roland A. Fleck, Gillian P. Bates, and Manolis Fanto in Current Biology. Published online November 22 2017 doi:10.1016/j.cub.2017.10.054