Download Background. We previously mapped an autosomal recessive form of

Title: Dense Core vesicle defect underlies the pathogenesis of ALS5
Additional authors (in order):Han-Xiang Deng, Yong Shi, Hong Zhai, Eileen H Bigio,
Nailah Siddique
Institution name, city, state, country of additional authors:
Background. We previously mapped an autosomal recessive form of ALS (designated as ALS5)
to a 6cM minimum candidate region between D15S146 and D15S123 on chromosome 15 using
three inbred kindreds from Tunisia. The defect and pathogenic mechanism underlying this ALS
remain to be elucidated.
Hypothesis. Loss of function mutations in a gene in this 6cM minimum candidate region cause
ALS5.
Methods. Whole-exome sequencing and Sanger sequencing were used to identify mutations in
juvenile ALS patients. Immunocytochemistry, immunohistochemistry and confocal microscopy were
employed to characterize the ALS5-linked protein and pathology of an ALS5 autopsy sample. An
autopsied case of ALS5/SPG11 was examined
Results to Date. We identified three homozygous mutations in the gene KIAA1840 in all three
original ALS5-linked families from Tunisia. In addition, we identified six premature stop
codon/frameshift and missense mutations (R93AfsX25, Q811X, E1819AfsX10, S1923RfsX28,
Y2404X and C2405S) in KIAA1840 in homozygous or compound heterozygous condition in six
juvenile ALS patients from four North American families. KIAA1840 encodes spatacsin and was
previously linked to autosomal recessive spastic paraplegia 11 (SPG11). The physiological function
of spatacsin remains unknown. We found that spatacsin co-localizes with large dense core vesicle
markers, suggesting that spatacsin may regulate the function of the large dense core vesicles, and
dysfunction of the large dense core vesicles may underlie the pathogenic mechanisms of
ALS5/SPG11. We further identified a unique type of membrane-associated inclusion bodies in the
motor neurons in the autopsy sample of an ALS5/SPG11 patient. These inclusions are ubiquitinand p62-positive, and also chromogranin A-positive, but SOD1-, FUS- and TDP43-negative.
Discussion/conclusions. Dense core vesicle, a regulated secretory vesicle like synaptic vesicle,
has never been directly linked to ALS, motor neurons or related disorders. We show evidence that
KIAA1840-encoded spatacsin is a transmembrane protein of dense core vesicles. Our findings
directly link dense core vesicles defects to motor neuron degeneration in ALS, suggesting a novel
pathway in the pathogenesis of motor neuron degeneration in ALS.