Mucopolysaccharidosis type II is often associated with challenging, disruptive behaviour and varying rates of cognitive decline. However, the underlying mechanisms are only poorly understood.
Now, several teams from Padova, Italy, have published findings that shed new light on this area. They performed an analysis of the MPS II mouse brain, using RNA sequencing (RNA-Seq). A detailed description is beyond the scope of this post, but basically RNA-Seq is an example of next generation sequencing that is widely used to study gene expression by transcriptome profiling. The transcriptome is the complete set of transcripts in a cell, and their quantity, for a specific developmental stage or physiological condition. Understanding the transcriptome is essential for interpreting the functional elements of the genome and revealing the molecular constituents of cells and tissues, and also for understanding development and disease.
The researchers investigated genes known to be involved in many aspects of neurological function. They found that there was dysregulation of many of these genes, for example calcium homeostasis, axon guidance, mitochondrial function, oxidative stress and circadian rhythm.
Several of these, for example mitochondrial function and oxidative stress, are involved in different stages of the Parkinson Disease pathway. A particularly important finding was the upregulation of alpha-synuclein, the accumulation of which is responsible for synucleopathies such as Parkinson’s disease (PD). For many years, Gaucher disease was the only lysosomal storage disorder (LSD) thought to be associated with PD. However, in recent years such as association has been described in other LSD’s such as Niemann-Pick disease type I and sphingomyelinase deficiency. Accumulation of alpha-synuclein has been demonstrated in the cortex of patients with MPS III. While PD has not yet been described in MPS II patients, it seems that it is only a matter of time before such an association is reported.
Alpha-synuclein also contributes to the development of Alzheimer’s disease. Its accumulation may therefore be of relevance to the cognitive decline that is seen in many MPS II patients.
It is quite possible that patients with MPS II will be found to have similar patterns of gene dysregulation to those seen in the mouse model. Were this to be found to be the case, it may well have implications for counselling and management.
However, a note of caution is required. The MPS II mouse has a single mutation; whereas human MPS II is caused by many mutations in the IDS gene. So even assuming that similar gene dysregulation to that seen in the mouse will be seen in human MPS II, we dont know how this will be linked to the individual mutations seen in patients. For example, will the gene controlling circadian rhythm be affected more severely in patients with certain MPS II mutations than others?
We also need to bear in mind that, while some aspects of human behaviour may be controlled by the genome, others may well be related to as yet unidentified epigenetic factors. Epigenetics is the term given to the modification of gene expression rather than the genetic code itself. The human epigenome has not yet been fully characterised; work on this is under way.
It may therefore be some time before we have answers to these important questions. Nevertheless, these are important findings that are likely to greatly improve our understanding of the complex neurological and neuropsychiatric features seen in MPS II.