Loss of the Tpp1 gene is associated with brain inflammation and nerve cell dysfunction, possibly due to oxidative stress — the cellular damage that occurs as a consequence of high levels of oxidant molecules — a mouse study says.
The study, “Global Brain Transcriptome Analysis of a Tpp1 Neuronal Ceroid Lipofuscinoses Mouse Model,” was published in ASN Neuro.
Neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, comprise five childhood genetic neurodegenerative lysosomal storage disorders characterized by vision loss, lack of motor coordination, and impaired cognition.
In human patients, late infantile Batten disease, also known as CLN2 disease, is caused by genetic mutations in the TPP1 gene, which provides instructions to make an enzyme called tripeptidyl peptidase 1 (TPP1). This enzyme is normally found in lysosomes — the cellular compartments that digest and recycle different types of molecules — where it helps break down unnecessary proteins. However, when TPP1 malfunctions, these proteins start to build up inside cells, reaching toxic levels and leading to the onset of disease.
In this study, researchers from the University of Chicago set out to examine the transcriptome (the group of all RNA molecules, or transcripts, produced from active genes in a cell or tissue) signature of nerve cells in the absence of Tpp1 (the mouse gene equivalent to the human TPP1).
Investigators performed a technique called RNA sequencing using brain tissue samples from 4-month-old mice that had been genetically modified to be unable to produce TPP1, thereby mimicking the human CLN2 disease.
Transcriptome analysis identified a total of 510 and 1,550 RNA molecules that were differentially expressed in different brain regions of mice lacking Tpp1, compared to age-matched healthy mice, respectively.
Analysis of differentially expressed genes in samples from animals lacking Tpp1 showed that microglia and astrocytes (two types of nerve cells involved in neuronal survival and brain injury repair) had an increased expression of genes involved in brain inflammation, which can lead to nerve cell dysfunction.
Gene expression is the process by which information in a gene is synthesized to create a working product, such as a protein.
Likewise, other genes involved in oxidative stress (e.g., production of nitric oxide and reactive oxygen species), immune cell activation and brain infiltration were abnormally increased in samples from mice lacking Tpp1.
Conversely, the expression of genes involved in the control of the circadian rhythm (the biological day/night cycle) was abnormally low in diseased animals.
“In summary, this study highlights the prominent involvement of neuroinflammation and oxidative stress in the development of NCL due to lack of TPP1 activity,” the researchers stated.
“Considering the extensive involvement of microglia, astrocytes, and endothelial cells [cells that made up the lining of blood vessels] in [disease development], neuroinflammation, and neurodegenerative process, and that they are themselves compromised in their function due to the lack of TPP1, it is important to establish their potential as therapeutic targets for this disease,” they concluded.