Ageing is characterised by a decline in function at both the cellular and organismal level and is the major risk factor for several neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease. One of the key cellular processes that is affected during ageing is the transport system that nerve cells use to deliver components to different locations.
Cytoplasmic dynein-1, a protein that transports cargos along microtubule tracks throughout the cell, binds to dynactin and cargo adaptor proteins to carry its cargos over long distances. Various cargos use different adaptors to recruit dynein for transport. Until now, it has not been clear whether all cargos recruit dynein in the same way and how different cargo adaptors act.
Previous work from KJ Patel’s group in the LMB’s PNAC Division revealed that aldehydes – such as acetaldehyde, a by-product of alcohol metabolism – can damage our DNA. Further research by the group showed that our cells are protected against these toxic aldehydes using a two-tier protection system: enzymes that remove these aldehydes (tier-1) and DNA repair that fixes the damage they cause (tier-2).
The human genome encodes approximately 5000 membrane-embedded proteins that carry out many essential processes such as cell-to-cell communication, cell adhesion and intracellular trafficking. Almost all of these proteins are assembled at the endoplasmic reticulum (ER) by molecular machines that guide them into the membrane. Because these thousands of membrane proteins are highly diverse in size, shape and charge, different machines are needed for different types of membrane proteins.
All the cells in our body contain thousands of proteins, molecular machines which carry out almost all biological processes that are essential for life. Many diseases, such as cancer and neurodegeneration, are caused when these protein machines go wrong. Thus it has been a long-term goal in science to characterise the functions of proteins within our cells.
The spliceosome is a molecular machine that plays an important role in gene expression. It cuts non-coding sequences (introns) out of messenger RNA (mRNA) precursors, and stitches together the useful coding sequences (exons). The spliceosome performs this in two steps. First, the start of an intron is recognised, cut, and joined to a specific point in the middle of that intron, forming a lasso-like looped structure.
Internal body clocks, which time the length of a day in almost all organisms, control many aspects of human physiology and activity, from when we go to bed to when we perform best mentally and physically. Most importantly, these biological circadian clocks are in every single individual cell of our bodies, not just in the brain.
Parkinson’s disease (PD) is a neurodegenerative condition caused by the loss of dopaminergic neurons in the midbrain, which manifests clinically in the form of characteristic motor defects. Most PD cases are sporadic and found in people above the age of 60. However, roughly 10% of PD cases are autosomal recessive juvenile forms (AR-JP), causing early-onset PD. It is known that mutations in PARK genes are responsible for this, but often a molecular explanation is lacking.
Inside our cells there are many distinct membrane compartments – organelles – which carry out the different tasks that allow the cell to function. Each organelle is like a factory that requires a constant supply of raw materials to stay active. Small transport vesicles deliver this cargo of particular proteins and lipids to each organelle.
Genes are encoded in DNA and need to be copied into an intermediate mRNA molecule that contains the instructions to allow synthesis of protein. Almost every mRNA has a repetitive sequence at one end called a poly(A) tail. The length of this tail specifies the amount of time that the mRNA is present in the cell, and how often it is translated into protein. Errors or changes in the tail are found in human diseases including β-thalassemia, thrombophilia and cancer, as well as viral infections.