Reducing waste: decreasing protein “refuse sack” build-up in dementia

Scientific title: Does lowering futile autophagosome synthesis alleviate aggregation-prone protein toxicity in dementia?

Type of project: Research grant

What do we already know?

Autophagy is an important cellular “self-eating” process that promotes cell survival through recycled nutrition and energy.  Autophagy also cleans up protein aggregates that can be toxic to neurons, causing neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.  The autophagy process involves two steps: collection of proteins into autophagosome (i.e. “refuse sacks”) and disintegration of these by acidic lysosomes.

In some dementia cases, the build-up of toxic protein aggregates cause an increase in autophagosome sacks of protein, but defective break down by lysosomes.  This leads build-up of “futile autophagosomes” that are toxic to cells – known as futile autophagosome synthesis (FAS).

What is this group trying to find out?

Using various human and mouse model cell lines for Huntington’s disease expressing the mutant Huntington (mHTT) protein, the group will use partially knock-down genes involved in synthesising autophagosomes to see if this alleviates the futile autophagosome build-up associated with mHTT.  Reducing FAS in a cell model of Parkinson’s disease and dementia with Lewy bodies (which expresses the toxic α-synuclein protein) to see if this diminishes toxicity will also be assessed, to investigate whether a common pathological mechanism exists across dementia conditions.

Using induced pluripotent stem (iPS) cells from Huntington’s disease patients, the use of anti-sense oligonucleotides (ASOs – a method of genetic knockdown currently showing promise in clinical trials) in reducing FAS and cellular toxicity will also be examined.

How do they do this?

A combination of genetic manipulations on various human and mouse cell lines will reduce FAS, cell toxicity assays will be used to see if these increase cell survival.

Why is it important?

This research will pave the way for in vivo research into reducing FAS and cellular toxicity, which could lead to novel treatments for Huntington’s disease.  Moreover, if these techniques also work for Parkinson’s disease then it may aid development of treatments for this disorder as well.

Further information

Please click here for more information about the work of Dr Shouquing Luo.

Please click here for more information about the work of Dr Oleg Anichtchik.