DCTN1 mutations in Perry syndrome

Abstract

Perry syndrome consists of early-onset parkinsonism, depression, severe weight loss and hypoventilation, with brain pathology characterized by TDP-43 immunostaining. We carried out genome-wide linkage analysis and identified five disease-segregating mutations affecting the CAP-Gly domain of dynactin (encoded by DCTN1) in eight families with Perry syndrome; these mutations diminish microtubule binding and lead to intracytoplasmic inclusions. Our findings show that DCTN1 mutations, previously associated with motor neuron disease, can underlie the selective vulnerability of other neuronal populations in distinct neurodegenerative disorders.

Figure 1. Pedigrees with Perry syndrome and DCTN1 mutations

Filled symbols indicate affected individuals with age of symptom onset beneath. A + indicates DNA was available at the time of study. To protect confidentiality some individuals are not shown and gender is portrayed using a diamond.

Figure 2. Dynactin and TDP-43 pathology in Perry syndrome

Dynactin p150 antibodies are not useful for immunohistochemistry. Dynactin subunits p50 and p62 (that may also exist as unbound monomer 5) stain inclusions with the same morphology and distribution as TDP-43. However, double immunostaining for p62/TDP-43 and p50/TDP-43 shows p62 and p50 are in ≤5% of the TDP-43 positive inclusions. In contrast, only a very small number of inclusions are positive for only p62, or only p50, and not for TDP-43. Panels a–f illustrate a range of p62 immunoreactive inclusions in the globus pallidus in Perry syndrome neuronal cytoplasmic inclusions (NCI) (a–d), neurites (e) and juxta-vascular glia (f), which are morphologically similar to inclusions detected in Perry syndrome with TDP-43 immunohistochemistry . Double immunohistochemistry for p62 (blue chromogen in g–j) and TDP-43 (brown chromogen in g–j) demonstrate that some NCI are double labeled (i), while others show predominantly p62 (g) or TDP-43 (h). Granular axonal spheroids show a heterogenous mixture of p62 and TDP-43 (j). Immunofluorescence with p62 (green fluorochrome) and TDP-43 (red fluorochrome) (k and l) shows a heterogenous mixture of p62 and TDP-43 in granular axonal spheroid (k) and complete overlap of fluorochromes (yellow) in a subset of NCI (l). Sections of substantia nigra double stained for p50 (blue chromogen in m–r) and TDP-43 (brown chromogen in m-r) demonstrates that some NCI (m–o) are double labeled (o), while others show predominantly p62 (n) or TDP-43 (m). Similarly, some neurites (p–r) are double labeled (r), while others show predominantly p62 (q) or TDP-43 (p). [g–i, m–r are 100x, all others images are 40x].