Interestingly, amongst the seven genes that have been identified to cause the disease, most have housekeeping functions, including small heat shock proteins (sHSP) (dHMN-II); glycyl tRNA synthetase (GARS) (dHMN-V); Berardinelli-Seip congenital lipodystrophy (BSCL2) (dHMN-V); immunoglobulin [micro]-binding protein-2 (IGHMBP2) (dHMN-VI); dynactin (DCTN1) (dHMN-VII); and senataxin (SETX) (dHMN) with pyramidal tract signs.
Abbreviations BSCL2: Berardinelli-Seip congenital lipodystrophy CMT2D: Charcot-Marie-Tooth 2D DCTN1: Dynactin subunit 1 dHMN: Distal hereditary motor neuropathies dSMA-V: Distal spinal muscular atrophy type V dSMA-Va: Distal spinal muscular atrophy type Va EMG: Electromyography ETC: Mitochondrial respiratory chain enzyme analysis GARS: Glycyl tRNA synthetase IGHMBP2: Immunoglobulin [mu]-binding protein-2 L: Leucine R: Arginine SETX: Senataxin sHSP: Small heat shock proteins SMA: Spinal muscular atrophy RSV: Respiratory syncytial virus VUS: Variant of unknown significance WES: Whole exome sequencing.
Among these, one of the striking observations is the differential expression of numerous ALS-linked genes (i.e., ANG, DCTN1, SQSTM1, and TBK1) involved in autophagy, a highly conserved and tightly regulated cellular self-degradative process whose alteration leads to an impaired clearance of toxic protein aggregates and/or of damaged mitochondria that represent some of the best characterized hallmarks of both SALS and FALS .
Abbreviations SOD1: Superoxide dismutase 1 ALS2: Alsin SETX: Senataxin SPG11: Spastic paraplegia 11 FUS: Fused in sarcoma RNA binding protein VAMP: Vesicle-associated membrane protein VAPB: Associated protein B and C ANG: Angiogenin TARDBP: TAR DNA-binding protein FIG4: FIG4 phosphoinositide 5-phosphatase OPTN: Optineurin ATXN2: Ataxin-2 C9ORF72: Chromosome 9 open reading frame 72 VEGF: Vascular endothelial growth factor IFN-[gamma]: Interferon gamma TNF-[alpha]: Tumor necrosis factor ILs: Interleukins IL-1[beta]: Interleukin 1 beta UBC: Ubiquitin C TBK1: TANK-binding kinase 1 SQSTM1: Sequestosome 1 DCTN1: Dynactin subunit 1 IMPAS-1: Histocompatibility minor 13.
We have also observed the downregulation of many genes involved in mitochondrial transport such as the family of dynactins (DCTN1
, 2, 3, 5, and 6), dyneins (DYNC1H1, DYNC1I1, and DYNC1LI1), kinesins (KIF1B and KIF5C), and Miro (data not shown).
During the study, the researchers found that Perry syndrome patients have mutations in a subunit of the dynactin complex (DCTN1; p150glued), which is essential to the movement of molecular "cargo" inside brain cells, or neurons.
Upon studying the eight families with Perry syndrome, the Mayo-led team found that each family had one of five novel mutations in the DCTN1 gene, whose protein produces a large subunit of the dynactin complex known as p150glued.