Spatial transcriptomics identifies dysregulated programs across neural and non-neural tissues in spinal muscular...

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder caused by insufficient survival motor neuron (SMN) protein.
• SMA leads to motor neuron degeneration and profound muscle weakness, but its multisystemic nature and early pathological programs are not fully understood.

Purpose of the Study:

• To investigate the early, tissue-wide transcriptional consequences of SMN deficiency in pre-symptomatic SMA mice.
• To define the pathological programs in neural and peripheral tissues affected by SMA.

Main Methods:

• Spatial transcriptomics was applied to lumbar spinal cord cross-sections from pre-symptomatic SMA and control mice.
• Analysis covered spinal cord, dorsal root ganglia, muscle, bone, cartilage, bone marrow, adipose, and connective tissues within their native anatomical context.

Main Results:

• SMA spinal cords showed motor neuron-associated upregulation of neurofilaments and microtubule machinery.
• Multiple tissues exhibited extracellular matrix gene dysregulation; skeletal muscle showed fiber-type-specific stress responses.
• Bone and bone marrow displayed osteoclast activation and immune signaling, while adipose tissue showed profibrotic signaling and lipolysis.

Conclusions:

• SMN deficiency drives early transcriptional reprogramming across multiple tissues before significant motor neuron loss.
• Identified non-neuronal pathological programs in SMA provide potential therapeutic targets for improving patient outcomes.