Neuronal railways: identifying the mechanism behind dysfunctional protein transport in dementia

Scientific title: Investigating the influence of the KLC gene polymorphism rs8702 in Alzheimer's disease pathology

Type of project: Pilot Project

What do we already know?

In order for neurons to work properly, proteins and other structures are transported to where they are needed within the cell.  For instance, proteins involved in the function of synapses (chemical junctions between neurons) are made in the cell nucleus and are transported (often long distances) to the synapse.  These transport mechanisms are complex and rely on “motor proteins”.  Motor proteins bind to specific protein cargoes and carry them on microtubules (essentially railway track-like structures) to where they are needed.

KIF5A is a motor protein that binds to KLC1 (kinase light chain) to transport proteins involved in Alzheimer’s disease.  It is known that a gene variation in KLC1 gene is linked to Alzheimer’s disease, and can predict conversion from mild cognitive impairment (MCI) to Alzheimer’s disease.  Reduced or dysregulated function of KLC1 may cause a compensatory increase in KIF5A expression, to improve the clearing of protein aggregates involved in Alzheimer’s disease.

What is this group trying to find out?

The interactions between KIF5A (the motor proteins), microtubules (the “rails”) and KLC1 (the link that binds the motor proteins to the microtubules) are still unclear.  This study aims to determine how the KLC1 gene variation affects the expression of KIF5A and KLC1, as well as the transport of Alzheimer’s disease-related proteins such as APP and amyloid-β.  This may help determine why some Alzheimer’s disease sufferers have a much more severe disease course than others. 

How do they do this?

Genetic analysis of human brain tissue from Alzheimer’s disease sufferers and healthy age-matched controls (without any cognitive impairment) will be used from the South West Dementia Brain Bank.  RNA and protein will be extracted from human tissue, KLC1  and  KIF5A  expression  will  be  analysed  based  on  genotype  and  correlated  with  common markers of AD neuropathology, such as amyloid-β and tau levels.

Why is it important?

Defective protein transport appears to precede protein aggregation, and therefore may represent a “window of opportunity” for preventing pathological aggregates.  Improving our understanding of the interactions between KIF5A, KLC1 and microtubules – and how these are affected by genetic variations linked to Alzheimer’s disease – may help us discover novel neuroprotective mechanisms and develop potential drug treatments.

Further information

Please click here for more information about the work of Dr Alastair Wilkins.

Please click here for more information about the work of Prof Seth Love.

Please click here for more information about the work of Dr Kelly Hares.