Volume 44, Issue 4, Pages (November 2004)

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Volume 44, Issue 4, Pages 601-607 (November 2004) Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology Alexander Zimprich, Saskia Biskup, Petra Leitner, Peter Lichtner, Matthew Farrer, Sarah Lincoln, Jennifer Kachergus, Mary Hulihan, Ryan J. Uitti, Donald B. Calne, A.Jon Stoessl, Ronald F. Pfeiffer, Nadja Patenge, Iria Carballo Carbajal, Peter Vieregge, Friedrich Asmus, Bertram Müller-Myhsok, Dennis W. Dickson, Thomas Meitinger, Tim M. Strom, Zbigniew K. Wszolek, Thomas Gasser Neuron Volume 44, Issue 4, Pages 601-607 (November 2004) DOI: 10.1016/j.neuron.2004.11.005

Figure 1 Pedigree Structure of the Two Largest Kindreds with LRRK2 Mutations Shown are family A (German-Canadian) and family D (Western Nebraska). Blackened symbols denote affected family members. An asterisk denotes a genotyped individual, with “m” for mutation carriers and “wt” for wild-type LRRK2. To maintain confidentiality, genotypes of some unaffected individuals in families A and D are not shown. Additionally, the structure of the pedigrees has been altered, and the genders of individuals in some of the youngest generations have been disguised. Neuron 2004 44, 601-607DOI: (10.1016/j.neuron.2004.11.005)

Figure 2 Pedigree Structures of Smaller Families with LRRK2 Mutations Blackened symbols denote affected family members. An asterisk denotes a genotyped individual, with “m” for mutation carriers and “wt” for wild-type LRRK2. To protect confidentiality, the genotypes of some unaffected individuals of family 469 are not shown. Additionally, the structure of the pedigrees has been altered, and the gender of individuals in the youngest generations has been disguised. Neuron 2004 44, 601-607DOI: (10.1016/j.neuron.2004.11.005)

Figure 3 Structure of LRRK2 (A) Axon positions. (B) Schematic drawing of LRRK2, with domains, primer positions for cDNA amplification, and positions of mutations. (C) Protein alignment of three mutations conserved among the following: hs, Homo sapiens; mm, Mus musculus; rn, Rattus norvegicus; ce, Caenorhabditis elegans; and dm, Drosophila melanogaster. Neuron 2004 44, 601-607DOI: (10.1016/j.neuron.2004.11.005)

Figure 4 Transcript Levels of LRRK2 in Different Human Tissues Quantitative RT-PCR assays show no differential expression of three regions of the LRRK2 transcripts within the same tissue. Transcript levels are given as ratios of LRRK2/h-PBGD, a low-copy housekeeping gene, normalized to adult whole brain expression as 100%. Note the comparably high expression levels of LRRK2 transcripts in putamen and substantia nigra, brain regions vulnerable to neurodegeneration in PD. Neuron 2004 44, 601-607DOI: (10.1016/j.neuron.2004.11.005)

Figure 5 Substantia Nigra Pathology in Families A and D Summary of substantia nigra pathology in six autopsies from family A (III:29, [A]–[D]; II:27, [E] and [F]) and family D (III:20, [G]–[J]; III:14, [K] and [L]; III:21, [M]–[O]; and IV:20, [P]–[R]). Three cases had nonspecific neuronal loss and gliosis in the substantia nigra (hematoxylin and eosin stain) (A and P) with ubiquitin-immunoreactive neuronal lesions. Ubiquitin immunohistochemistry revealed a range of lesions, including irregular cytoplasmic inclusions (arrow in B) (B and D), curvilinear dystrophic neurites (C and E), granular and foamy axonal spheroids (R), and multiple nuclear inclusions (arrows in D and Q) (D, F, and Q). α-synuclein immunohistochemistry was positive in two individuals, showing many cortical Lewy bodies (G) and cortical Lewy neurites (H) in one case, as well as typical brainstem-type Lewy bodies (arrow in I, K, and L) or pleomorphic Lewy bodies (J) in the substantia nigra and brainstem nuclei. One case had tau-immunoreactive lesions similar to those seen in PSP, including globose neurofibrillary tangles (M and N), tufted astrocytes (arrow in M), and oligodendroglial coiled bodies (M and O). Neuron 2004 44, 601-607DOI: (10.1016/j.neuron.2004.11.005)