Global Brain Transcriptome Analysis of a Tpp1 Neuronal Ceroid Lipofuscinoses Mouse Model.

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Homozygous mutations in the TPP1 gene cause late infantile neuronal ceroid lipofuscinoses in humans due to loss of tripeptidyl peptidase 1 (TPP1) activity.
• A mouse model mimicking human TPP1 deficiency exhibits similar pathology and clinical features, making it suitable for studying transcriptional changes.

Purpose of the Study:

• To analyze end-stage transcriptional alterations in the brain of Tpp1-deficient mice lacking TPP1 enzymatic activity.
• To identify specific gene expression changes and affected biological pathways associated with TPP1 deficiency.

Main Methods:

• RNA sequencing was employed to compare gene expression in the forebrain/midbrain and cerebellum of 4-month-old Tpp1-deficient mice and control littermates.
• Ingenuity™ pathway analysis was used to interpret differentially expressed genes.
• Quantitative polymerase chain reaction and mRNA in situ hybridization were utilized for validation and anatomical analysis.

Main Results:

• Significant transcriptional changes were observed, with 510 and 1,550 gene transcripts altered in the forebrain/midbrain and cerebellum, respectively.
• Increased neuroinflammation involving microglia and astrocytes, elevated nitric oxide and reactive oxygen species production, and activated complement pathways were identified.
• Downregulation of transcription factors controlling circadian rhythm was also noted.

Conclusions:

• TPP1 deficiency leads to widespread transcriptional dysregulation in the brain, characterized by neuroinflammation and disrupted circadian rhythm.
• These findings highlight potential mechanisms underlying neuronal dysfunction in TPP1-related disorders.
• The identified differentially expressed genes provide novel avenues for therapeutic target discovery for neuronal ceroid lipofuscinoses.