Spg7-flox Mouse

Spg7, also known as paraplegin, encodes a mitochondrial metalloprotease. Under normal physiological conditions, the inner mitochondrial membrane proteins, AFG3L2 and SPG7, are tethered to prohibitin 1 (PHB1) to inhibit the opening of the mitochondrial permeability transition pore (mPTP) [1]. SPG7 is associated with hereditary spastic paraparesis, a group of inherited neurological diseases with wide genetic heterogeneity, especially when associated with cerebellar ataxia [2].

Compound heterozygous mutations in SPG7 have been found in patients with cerebellar degeneration, ataxia, and impaired emotional communication, expanding the phenotypic boundary of SPG7 [3]. In a cohort of patients with hereditary ataxia, SPG7 was among the most common causative genes [4]. Heterozygous SPG7 mutations have been identified in amyotrophic lateral sclerosis (ALS) patients, and these patients more frequently presented with cerebellar symptoms, flail arm or leg syndrome, and showed partial clinical overlap with hereditary spastic paraplegia (HSP) [5]. SPG7 pathogenic variants can also cause autosomal recessive hereditary spastic paraplegia, and various ophthalmological findings have been reported in patients with spastic paraplegia type 7 [6]. Additionally, SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases [7].

In conclusion, Spg7 is crucial for maintaining mitochondrial function by regulating mPTP opening. Studies on Spg7-related genetic mutations in various diseases, such as hereditary spastic paraparesis, cerebellar ataxia, and ALS, have deepened our understanding of the gene's role in these neurological disorders. These findings provide insights into the underlying mechanisms of these diseases and may potentially guide future therapeutic strategies.